Nano-based drug delivery system: a smart alternative towards eradication of viral sanctuaries in management of NeuroAIDS

Even though the dawn of highly active antiretroviral therapy (HAART) proved out to be a boon for acquired immunodeficiency syndrome (AIDS) patients, management of HIV infections persists to be a major global health curse. A reduced efficacy with existing conventional therapy for brain targeting has been largely credited to the inability of antiretroviral (ARV) drugs to transmigrate across the blood-brain barrier (BBB) in productive concentrations. The review consists of nano-based drug delivery strategies rendering superior outcomes to delivery of ARV drugs to the viral sanctuaries in the brain. Nano-ART for ARV drugs promotes the development of an optimized dosage regimen, thereby improving the penetration of drugs across the BBB in an attempt to target the central reservoirs hosting viral population. Numerous efforts have been undertaken for making the drug more bioavailable and therapeutically effective by moulding them into various nanostructures. Polymeric nanocarriers, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, nanodiamonds, vesicle-based drug carriers, metal-based nanoparticles, and nano vaccines have been reported for their advancing role as a smart alternative for drug delivery to central nervous system. The high drug loading capacity of nanocarriers and their small size effectuating increased surface to volume ratio is accountable for improved efficacy of ARV drugs when formulated as nanotherapeutics. This review highlights the advancing role of nanotherapeutics in mediating a successful delivery of ARV drugs to eradicate viral loads in treating NeuroAIDS.


Introduction
The HIV epidemic has emerged as a global issue affecting approximately 38.0 million population worldwide making acquired immunodeficiency syndrome (AIDS) one of the leading causes of illness-related death [1]. The subsequent events of immune system deficiency following the encounter with human immunodeficiency virus (HIV) infection are linked to a range of associated infectious including the risk of degenerative disorders, and inflammatory traumas [2]. According to the global estimates of 2019, 1.7 million new HIV infections and 690,000 AIDS-related casualties were reported across the world [1]. Though the current scenario of global HIV infection is changing with increased access to ARV therapy, an approximate of 4500 new HIV infections are reported per day [3,4]. Eastern Europe and Central Asia rank among the top regions in the spread of the HIV epidemic with a higher prevalence ratio of 10.1 as compared with any other region. A wide gap between HIV testing and treatment commencement is the major reason behind the widespread disease in such regions. Also, the issues of social and community-based biases faced by lesbian, gay, bisexual, transgender, and intersex (LGBTI) people and also higher incidents of sexual violence among women have impeded the allocation of HIV services. As per the Global AIDS update-2019, women of age group 15-24 accounts for 6200 newly infected HIV cases per week [3]. Signs of chronic inflammation persist in a large percentage of treated patients due to the presence of undetectable latent reserves of the virus [5]. Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) continue to remain a frequent manifestation of viral infection affecting nearly half of the HIVpositive population [2,6]. HIV-infected CD4+ T cells and monocytes are the potential invaders of the central nervous system (CNS) at an early phase of infection. Soon it was realized that HIV can form reserves in the brain inducing several motor and cognitive disorders leading to behavioural changes and neurodegeneration. When described cumulatively, neurodegeneration and the related neurological complications were termed as NeuroAIDS [7].
Combined antiretroviral therapy (cART) inhibits the virus replication but does not cease the disease due to reactivation of infectious HIV-1 genome from their latent reservoirs after the treatment is withdrawn [5]. Neurocognitive disorders associated with HIV-1 infection are known to haunt more than half of the population living with HIV under retroviral therapy [8]. Co-morbidities following HIV infections, viz., drug abuse, co-infections, degeneration, and psychiatric alterations amplify the risks and burdens of HAND [9]. As CNS serves as a reservoir for HIV, efficient approaches to decimate persistent HIV in the Central Nervous System can lead to substantial management of HIV.
Despite highly efficacious antiretroviral (ARV) drugs, only partial restoration of the immune system is observed with highly active antiretroviral therapy (HAART) [10]. The 39% shrinkage has been reported in the total AIDSrelated deaths since 2010; still, there are challenges to overcome for complete eradication of the accumulated viral reserves in various body parts [3].
A major setback to successful brain delivery of conventional HAART may be due to the inability of ARV drugs to cross the blood-brain barrier (BBB), efflux by P-gp transporters, extensive first-pass metabolism, or gastrointestinal degradation [11]. Also, the long-term therapy and complicated dosage regimen result in a lack of patient compliance leading to non-adherence to the HAART. Nano-based drug delivery system has been explored to improve the therapeutic efficacy and reduce the systemic drug toxicity in the management of NeuroAIDS [12]. Nano-ART, i.e., antiretroviral laden nanoparticles pledge to deliver an optimized drug regimen via improving the CNS penetration of the drugs, thereby enhancing bioavailability. The high drug loading capacity of nanocarriers with an increased surface to volume ratio is responsible for the improved efficacy of the antiretroviral drugs as nanotherapeutics [13]. The review highlights the advancing role of nanotechnology for efficient drug delivery of antiretrovirals in the treatment of NeuroAIDS.
HIV and the brain: brain as a reservoir of HIV HIV, a neurotropic virus, is known to cause inflammationmediated damage to the subcortical region of the brain and other regions of the spinal cord. Only in 1985, the effects of HIV infection on the brain became evident as a consequence of recovered HIV from the brain tissue [14]. Brain autopsies in HIV-infected individuals also depicted impaired white and grey matter with a marked reduction in their net volume in frontal, parietal, and temporal lobes [15]. The brain can be observed to encounter HIV infection either through a cell-dependent or cell-independent/direct pathway. A highly selectively permeable blood-brain barrier (BBB) is known to protect the CNS and helps to regulate the brain's homeostasis. Brain microvascular endothelial cells (BMVECs) cemented to one another by tight junctions (TJs) are responsible for the restricted movement across the BBB [16].
The primary pathway concerned with the transmigration of HIV across BBB is through infected monocytes and lymphocytes. The virus-infected monocytes, microglial cells, and macrophages release nitric oxide (NO) which alters the integrity of the protective barrier present in the brain. Also, the presence of some viral factors including Nef and Tat are responsible for an enhanced cross-through of HIV into CNS by boosting rates of virus replication and its survival and by inducing apoptosis of the BBB respectively [17]. These viral proteins bind to various chemokine receptors and impart neuroinflammatory effect ("bystander effect") by activation of microglia, macrophages, and astrocytes [18]. The HIV1 strains that infect macrophages by targeting the CXCR5 on the CD4 cells are classified as macrophage-tropic (M-Tropic). The large occurrence of M-tropic HIV-1 R5 envelops in the brain favours the replication of HIV in macrophages and microglial cells making it a principal reservoir for the virus. The resultant multinucleated giant cells (MGCs) due to the fusion of infected T-cells and macrophages work as a highly reproducible virus generating machinery [19]. The latency of HIV generally develops during the period of low viral gene transcription activity only after the integration of the viral genome with the host genome [20]. The viral population inhabits certain longest living cells of the human body including astrocytes, macrophages, and microglial cells, thereby making them "sanctuaries" for the viruses [21].
Abuse of certain drugs like opiates (morphine, cocaine), nicotine, psychomotor stimulants, and alcohol has been shown to worsen the disease progression resulting in an aggravated expression of HIV [22]. Owing to the inevitable feature of viral rebound, many strenuous approaches are needed to eradicate the virus from the body. Upon the action of antiretroviral therapies, HIV tends to evolve into a better adapted and more neurotoxic form with an ability to spread through systemic circulation [23].

HAART: current status and pitfalls
In 2018, among 37.9 million of the world's collective HIV infected population, only 23.3 million were at access to antiretroviral therapy. Administration of either a single or a combination of different ARV drugs forms the basis of HAART [24]. Depicting improved survival rates among HIV positive patients, HAART has been extensively used for suppressing the progression of AIDS. Given at an early stage, ARV drugs are believed to decrease the viral load in CNS and to demote the occurrence of HIV-related neurocognitive illness [25]. HAART has been observed only to clampdown the advancement of HIV and not complete the termination of the disease [26]. Due to the "latent reservoirs" of HIV in the brain [20], slow and sustained replication of the virus continues to persist in CNS promoting the development of HIV-associated neurocognitive disorders eventually contributing to NeuroAIDS [16].
Following a long history of development, US Food and Drug Administration (USFDA) in 2018 has approved six classes of ARVs for treating HIV infection viz., nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, HIV integrase strand transfer inhibitors, and entry inhibitors [27]. FDA has also approved certain multiclass combination products that have been designed to target multiple stages of the life cycle of HIV at one time.
The major pitfalls associated with orally administered HAART comprise poor patient compliance due to complex dosage regimens, high pill burden, and undesirable taste. A lack of adherence to therapy leads to the development of resistant strains of the virus resulting in viral rebound [28]. Furthermore, high genetic diversity and the tendency for continuous mutations lead to the development of multidrug resistance (MDR) in viruses [20,29]. An integrated and non-fenestrated BBB limits the penetration of ARVs into the brain thereby, preventing access of the therapy to localized sites of HIV in the brain [29,30]. A majority of ARV drugs portray low solubility, extensive hepatic first-pass metabolism, and predictable gastrointestinal degradation challenging a successful oral drug delivery to the brain [28,29]. Some ARV drugs such as indinavir and ritonavir are potential substrates for P-gp efflux transporters and are effluxed out readily devoiding the brain from an effective concentration of drug [17]. Also, short half-lives and decreased residence time result in sub-therapeutic effects often leading to hepatotoxicity [31].
Apart from the limited permeability across BBB, various other challenges that impede the treatment of AIDS include a short half-life of many antiviral drugs, development of drug resistance, limited solubility and permeability of drugs, and the inability of the antiviral drugs to achieve access to anatomical target sites [32]. Also, the HAART does not play a significant role in coping up with the inflammatory degeneration caused due to HIV infection [22]. Antiviral drugs act by inhibiting the action of various proteins and enzymes that are involved in the HIV life cycle. ARV such as elvitegravir and raltegravir inhibits the integrase enzyme, thereby preventing the incorporation of viral DNA to the host DNA. Other ARV agents belonging to the class of reverse transcriptase inhibitors such as lamivudine (NRTI), zidovudine (NRTI), efavirenz (NNRTI), and nevirapine (NNRTI) act by inhibiting the formation of viral DNA from viral RNA via the process of reverse transcription. The ARVs, when given in combination, can act to target numerous HIV proteins or a similar protein [33].
Though the viral species tend to show rebound on the discontinuation or cessation of the therapy, complete eradication of HIV from body reserves is still an area of research and development. However, emerging research studies undergoing the development of therapeutic vaccines and tools for editing on the genetic levels can provide an absolute eradication option [34,35].

Nanotherapeutics in the treatment of neuroaids
Nanotechnology has transfigured current therapeutics through its unique potentials in the arena of biosensing, diagnosis and imaging, and therapeutics. A highly selective BBB restricts the movement of drugs into the brain when administered in conventional form resulting in diminished access of drugs to the brain. As an outcome, the low bioavailability of active molecules inside the brain permits aggravated viral proliferation which results in an accelerated progression of neuroAIDS. Nanoformulations have been largely explored to improve drug transport across BBB with an improved in vitro efficacy [36]. Drug-loaded nanotherapeutics aids in the transport of the drug across the BBB in adequate amounts to bring about establishing control over neuroAIDS [37]. New techniques and drug designing approach can help to overcome the drawbacks of low oral bioavailability and extensive hepatic metabolism related to ARVs [36]. Owing to their small particle size and increased surface to volume ratio, nanotherapeutics offers a promising approach as neurotherapeutics [16] in the management of NeuroAIDS. Nanocarriers possess the versatility of being modulated which makes them a reliable alternative to deliver ARVs across the BBB [20].
Lately, nano-based drug delivery techniques have expanded to a combinational drug dosage research. The rationale of combinational drug delivery system incorporating nanotechnology is to target a site of interest and promote extended drug stay for weeks with only a single dose. Also, different nano-based strategies, viz., polymeric nanocarriers, lipidic nanocarriers, nanoemulsions, nanodiamonds, and vesicle based systems, have been exploited for their potential to deliver a single therapeutic agent to the brain in treating NeuroAIDS. The role of miscellaneous nano-based drug dosage regimen in clearing the residual HIV in the central nervous system by enhancing the patient's adherence to the therapy has been briefed in Table 1 [38].

Polymeric nanoparticles
Polymeric nanoparticles (NPs) are fabricated from a core polymer matrix in which drugs can be incorporated with sizes usually between 60 and 200 nm [54]. Chitosan is the most widely used natural polymer. Synthetic polymers used for nanoparticle preparation may be in the form of preformed polymer, e.g., polyesters like PLA, polycaprolactone (PCL), or monomers that can be polymerized in situ, e.g., polyalkyl cyanoacrylate [55]. Polymeric NPs generate two kinds of structures based on the fabrication method: nanosphere and nanocapsule [56]. Polymeric NPs have significant advantages for drug delivery such as nontoxicity, non-immunogenicity, targeted drug delivery, biodegradability, and biocompatibility [55]. However, some polymeric NPs show disadvantages; e.g., chitosan-based NPs exhibit low water solubility, alginate-based NPs indicate bad biodegradability, and poly β-hydroxybutyrate (PHB) shows bad thermal stability and high crystallinity [57]. However, the benefits outweigh the risk making them an attractive approach for drug delivery. Polymeric NPs comprise a required capability for surface alterations with chemical transformations, give magnificent pk control, and are preferable for encapsulation and delivery of a broad range of beneficial drugs [58]. There are several mechanisms by which the uptake of the drug to the brain through polymeric NPs takes place as NPs help in holding the drug in blood-brain capillaries, the opening of the tight junction of BBB, and transcytosis of the drug through brain endothelial cells. Polysorbate coating is used to coat the polymeric NPs. These help to enhance the bioavailability of the drug by the mechanism such as solubilization of lipids and membrane fluidization, inhibiting the P-gp efflux system and through endocytosis [59]. The intra-nasal route can also transport polymeric NPs to the brain either with the olfactory route or trigeminal-neurons. Rapid drug delivery can be achieved with nasal epithelium. Para-cellular drug transportation occurs over the olfactory epithelium into peri-neural space and then to sub-arachnoid space and cerebrospinal fluid, from where then diffusion takes place into the brain tissues. In intra-cellular transport, drug uptake to olfactory-neurons occurs with the passive diffusion, receptor-mediated endocytosis, or adsorptive-endocytosis, followed by axonal transport. Another mechanism is the transportation of drugs to brain tissues from trigeminalneurons. In this mechanism, the drugs get traversed into the brain via respiratory-epithelium of the nasal cavity. They can enter either to the caudal-brain via the anterior lacerated foramen or the rostral-brain via the cribriform plate near the olfactory bulb [60].
Gong and associates formulated elvitegravir (EVG) into a poloxamer-PLGA nanoparticle (PLGA NPs) to achieve HIV-1 suppression in the CNS macrophages. A significant improvement in dose-dependent and timedependent penetration was observed in the in vitro BBB penetration model for EVG-PLGA-NPs when compared with EVG native drug as depicted in Fig. 1. On evaluating the p24 levels, importantly lower viral load was observed in macrophages of the central nervous system after crossing the BBB model with EVG-PLGA-NPs as compared with the plain EVG drug, thereby indicating better antiviral efficacy of the nanoformulation [61].
In another study, Martins and associates prepared Efavirenz loaded nanoparticles of poly-lactic-co-glycolicacid to treat HIV neuropathology. From in vitro study, it was observed that the nanoparticles fabricated by microfluidics method exhibit 50% sustained release of efavirenz in the early 24 h. Nanoparticles illustrated a positive response to the blood-brain barrier and neuronal cells; i.e., its metabolic activity > 70% and nonhemolytic property were also observed. In vitro permeability of efavirenz nanoparticles via the blood-brain barrier model was found to be 1.3 folds greater than the plain drug. From the research, it was confirmed that the polymeric nanoparticles have the potential for targeting the BBB to treat neuro disorders [62].
In another research, Dalpiaz and associates developed zidovudine (AZT) prodrug nanoparticle coated with In vivo biodistribution studies depicted an enhanced drug accumulation in the brain after 14 days. The plasma viral load was diminished to undetectable levels by 6 weeks of biweekly SC administration [39] Lactoferrin nanoparticles/per oral Zidovudine + Efavirenz + Lamivudine Proteinaceous ligand (Lf) A low hemolysis rate of < 2% depicted its nontoxic nature. In vivo PK studies resulted in higher C max . Also, high tissue distribution and less toxicity were observed in the brain [40] Long-acting parenteral nanoparticles/SC

Tenofovir alafenamide + Elvitegravir
Polymers forming organic phase (PLGA, PF-127) and the aqueous phase (PVA) The PK studies depicted a higher AUC for the nanoformulations as compared with free drugs in the brain. An in vitro synergistic action against HIV-1 was observed [41] Polymeric nanoparticles/per oral The combinational NP depicted a significant HIV-1 inhibition in both cultured T-cells and PBMCs. Also, the NP exhibits an increased drug loading along with enhanced in vitro release kinetics [42] Nanogel/Intravenous Zidovudine + Lamivudine + Abacavir Conjugated with a modified polycationic polymer (CEPL) A 10-fold viral inhibition was observed in infected MDM with nanogel. Due to small particle size and cationic nature, nanogel-drug conjugates are capable of eradicating HIV-1 infection in the brain [43] Nanosuspension/Parenteral Atazanavir + Ritonavir + Efavirenz Coated with surfactants (ethylene oxide, propylene oxide, P-188, DSPE-mPEG2000, DOTAP) An absolute suppression of HIV-1 p24 antigen expression on the 20th day of infected cells was observed. Nearly 1.5-twofold higher drug levels were attained along with an inhibition of virus replication up to 15 days from treatment [44] Bile-salt coated nanocores/intranasal Zidovudine prodrug (U-AZT) Coated with bile acid salts (taurocholate or ursodeoxycholate) A 70 times higher uptake by murine macrophage was observed in vitro with the nanocore vs. free drug. In vivo studies depicted a relatively high uptake (up to 4 μg/ml) of U-AZT in CSF when administered IN in the presence of chitosan [45] In situ hybrid nano-drug delivery system (IHN-DDS)/IV Nevirapine Lipids and surfactants (SA, P-188, PGDS) A biphasic in vitro release pattern of NVP was observed over 24 h. Bio-distribution studies depicted 3.7 folds increment in the brain levels of NVP-IHN-DDS after 1 h of administration [46]  values than the free drug. In vivo antiviral efficacy was established by a sixfold decline of HIV-1-infected cells in nano-AZT-treated mouse rather than the AZT alone [47] Tf-QD-Amprenavir nanoplex Amprenavir Mercaptosuccinic acid A successful transfer and uptake of the Tf-QD nanoplex across the in vitro BBB was observed. A 1.5-fold higher antiviral efficacy in HIV-1 infected monocytes was observed with the nanoplex [48] Surface-modified nanosuspension/parenteral Nevirapine Surface modification with serum albumin, polysaccharide and polyethylene glycol, dextran 60 A 3.84-fold increase in cellular uptake was depicted with nanosuspension. PK studies revealed higher levels of AUC 0-24 in the brain with AUC brain /AUC blood ratio of 9.33.
The ability to traverse across BBB in less than 30 min indicates their potential in brain targeting [49] Nanostructured lipid carriers/per oral Atazanavir Precirol ATO 5, Lauroglycol 90, Cremophor RH 40 The pharmacokinetic studies established a 2.75fold enhancement in C max in the brain and fourfold augmentation in brain bioavailability suggesting the superiority of NLC formulation over drug suspension [50] Polymeric nanoparticles/per oral Dolutegravir Chitosan Improved stability and drug release were observed in the 0.1 N HCl when compared with pure drug. Again, the MTT assay and the Syncytia inhibition assay in C8166 (T-lymphatic cell line) infected with HIVIIIB viral strain demonstrated superior therapeutic efficiency and diminished cytotoxicity in comparison to the pure drug [51] Nanoparticles/intravenous Indinavir Lipoid E80 The studies exhibited robust drug levels and decreased HIV-1 replication in the brain [52] Nanoparticles/intravenous Darunavir Cholesterol, DSPC, DSPE-mPEG2000 An 8.99-fold increase in nanocarrier uptake was observed from darunavir nanoparticles than free darunavir in hCMEC/d3 cells. An increment of 3.38-5.93-fold in brain darunavir level was attained from nanoparticles over free darunavir [53] bile salt which modulates uptake of nanocores. In vitro study showed that the intake of nanoparticles coated with taurocholate by macrophages was greater than nanoparticles coated with urso-deoxycholate or plane U-zidovudine, i.e., ~ 500% and ~ 7000%, respectively. From In vivo experiments, it was found that AUC observed for U-zidovudine in cerebrospinal fluid following intranasal administration of nano suspension without chitosan was significantly lower, i.e., p < 0.0001 than observed for nanotauro with chitosan; therefore, chitosan depicts their capability for doubling the intake of U-zidovudine in cerebrospinal fluid when prodrug was prepared as nanotauro [63]. Another study was conducted by Patel and associates; they fabricated Lamivudine-loaded poly-lactic-coglycolic acid and mannosylated-PLGA (Mn-PLGA) NPs for targeting the macrophages cells of the brain. From in vitro study, sustained release of drugs in PBS and sodium acetate medium was observed for 6 days, as depicted in Fig. 2a. The in vivo study showed brain-to-plasma ratio for Mn-PLGA NPs and PLGA NPs was greater at every time point as compared with the plain solution of the drug. In Mn-PLGA NPs, the Lamivudine concentration was persistently increased up to 12 h which confirmed the successful delivery of drugs through the BBB to the brain as shown in Fig. 2b [64].
In another study by Belgamwar and associates, they prepared EFV nanoparticles (EFV-NPs) with the use of chitosan-g-HPβCD (hydroxypropyl-β-cyclodextrin) for enhancing the central nervous system intake of efavirenz via intranasal administration. A permeability study showed that the NPs had 4.76 times higher permeability than free drug solution. After intranasal administration of nanoparticles, 12.40-fold enhancement in CNS bioavailability of efavirenz as compared with i.v. solution, higher percentage drug targeting, i.e., 99.24% and drug targeting index, i.e., 141.3, was found. Nanoparticles also revealed histocompatibility and found nontoxic to the L929 cell line. Therefore, chitosan-g-HPbCD nanoparticles can be a good carrier for brain delivery [65].
In another research, Fiandra and associates fabricated antiretroviral drug enfuvirtide (Enf) nanoconstruct by using iron-oxide NPs coated with amphiphilic polymers [66]. The general targeting mechanism to reach an organ of interest of Iron oxide NPs is passive, active, and magnetic drug targeting [67]. These NPs enhance enfuvirtide translocation across the BBB in both in vitro and in vivo models. From this study, the conclusion was that nano constructs made up of polymers have the potential carrier for enfuvirtide for brain targeting [66].

Polymeric micelles
The polymeric micelles are made up of various molecules whose diameter range is 10-100 nm. These micelles are made up of two core shells, i.e., inner and outer core-shell. The inner core by nature is hydrophobic, and the outer core is hydrophilic. The formation of polymeric micelles is controlled by maintaining the balance between attractive and repulsive forces [68]. The dimensions of micelles are relying on a number of hydrophilic and hydrophobic chains and the number of amphiphile aggregation and molecular weight of amphiphilic copolymers [69]. The various advantages of polymeric micelles are due to their attractive attributes such as relatively high stability, biocompatibility, core-shell arrangement, less toxic, nano size, micellar association, and its morphology. Several kinds of clinical applications are provided by these nanocarriers, like solubilization of poorly dissolvable drug and protection of encapsulated drug [70]. Polymeric micelles can transport the drugs to the brain by conjugating with targeting ligands [71]. From research conducted by Roma and associates, it was found that polymeric amphiphile Tetronic 904 and gefitinib importantly inhibit the activity of pump and enhanced the aggregation of efavirenz in the central nervous system. Tetronic 904 comprising micelles controls the overexpression of ABCG2 in BBB, thus enhances the penetration of efavirenz into the central nervous system [72].

Solid lipid nanoparticles
Solid lipid nanoparticles (SLNs) are made by lipids such as triglycerides, fatty acid, and waxes. Along with lipid, emulsifier and water are also added. Along with solid lipid, emulsifier and water are also added. These NPs are less than a micron in size and act like another possible drug delivery system to emulsion and liposomes. SLNs comprise a hydrophobic matrix that is coated with phospholipids. Therefore, it is anticipated that these nanocarriers have larger encapsulation efficiency for hydrophobic drugs in their matrix core as compared with traditional liposomal nanocarriers [73,74]. Solid lipid nanoparticles (SLNs) having the advantage of site-specific targetability along with being able to be functionalized with specific moieties which would enhance the targeting potential to specific organs. It follows a controlled release mechanism [75]. It is also having the advantage of ease in scale-up and low cost of production and stability against coalescence or aggregation [74]. Due to the presence of lipids, uptake of these nanoparticles by the brain ia much easier. Hence, it can be a promising nanocarrier for brain-related disorders [76]. By functionalization of the solid lipid nanoparticles with targeting components such as protein, peptide, and antibody increase the penetration of the blood-brain barrier [77]. SLN functionalized with apolipoprotein E; i.e., ApoE may imitate lipoprotein-particles that enter into the BBB endothelium through endocytosis via low-density lipoproteins receptors and by transcytosis to the brain. These nanoparticles can also be transported via the intranasal route following the same pathways as that of polymeric NPs [78].
Research conducted by Lahkar and associates fabricated Kokum-butter SLNs coated with Polysorbate-80 for brain delivery of Nevirapine. Nanoparticles continue to exist in systemic circulation for 48 h keeping a sustained release in the brain for 24 h. From this research, it was confirmed that these nanoparticles could be a promising nanocarrier for brain-targeted delivery [79]. In another research, Gupta and associates fabricated solid lipid nanoparticles of efavirenz. In vitro release study revealed that there was an excellent drug release from solid lipid nanoparticle dispersion as compared with free drug suspension. The in vivo pk studies showed there was 150 times more brain targeting efficiency of the SLN formulation via intra-nasal route as a comparison with oral route suggested that these nanoparticles could be a promising carrier for brain delivery and cure of HIV [80].
In another research conducted by Joshy and associates, they prepared zidovudine-loaded SLNs of stearic acid (SA) altered with aloe-vera (AV) for brain targeting. In vitro drug release of zidovudine from altered stearic acid NPs was slow in comparison with the release of zidovudine from unaltered stearic acid NPs. In vitro cytotoxicity study revealed, at the same concentration, the zidovudine-SA and zidovudine-SA-AV did not show any sign of cytotoxicity against C6 glioma cells due to % survival of cell-lines and was > 90%. From the cellular uptake study, it was confirmed that the aloe-vera enables the up-take of NPs into the glioma-cells and also endorsed these NPs could have the potential to increase the uptake of the antiretroviral drugs by brain cells [81].

Nanostructured lipid carriers
Nanostructured lipid carriers (NLCs) are the second generation lipidic nanocarriers that comprise of solid and liquid lipids. They offer certain remarkable advantages over nanoemulsions that include immobilization of therapeutic drugs and prevention of coalescence of drug particles. Similarly, when compared with solid lipid nanoparticles, NLCs offer benefits such as enhancement in drug loading attributable to the presence of liquid lipids and increased imperfections in the solid matrix [82,83]. NLCs also enhance the chemical stability of encompassed drugs [84]. NLCs have the advantages over the SLNs, polymeric particles including biodegradability, less toxic, slow-release, drug safety, and excluding of organic solvents throughout the production. Over the past few years, nanostructured lipid carriers are also investigated for the delivery of hydrophobic and hydrophilic drugs [82,85].
NLC can be transported to the brain via oral or intranasal route. In the case of the oral route, NLC subjects to the digestion of lipid into monoglycerides (MG) and fattyacids (FA) by pancreatic enzymes exist in the duodenum and these MG and FA get enclosed by bile salt molecule for the formation of micelles which reaches to brush-border of enterocytes. The lipidic part combines with cholesterol and phospholipids to form chylomicrons, and then, these chylomicrons are subjected to exocytosis. Chylomicrons cannot go across the blood-capillaries due to their larger size; therefore, they go into via lacteals so that they can bypass the first-pass metabolism of the entrapped drug molecules after that intake of these chylomicrons into the glymphatic system of the brain take place followed by endocytosis with the help of selective endogenoustransporters and the opening of endothelial-tight-junctions in the brain. In the case of the intranasal route for targeted brain delivery, the same pathways are following by NLC as stated for polymeric NPs [60].
Sarma and associates optimized and fabricated tenofovir disproxil fumarate (TDF)-loaded nanostructured lipid carriers (NLCs). In vitro drug release study disclosed the release of drug from the formulation demonstrated a biphasic pattern showed by initial burst release followed by the sustained release in phosphate buffer saline pH 6.4, PBS pH 7.4, and ACSF. It can be concluded that the nanostructured lipidic carrier proves to have a potential for the brain-targeted delivery through intranasal route [86]. In another research, Pokharkar and associates developed an optimized Efavirenz-NLCs for brain targeting. From optimized formulation, 92.45% drug release was observed in 24 h revealed by in vitro drug diffusion studies. Singledose in vivo pharmacokinetic studies showed C max value of 31.45 ± 0.75 and t1/2 of 11.14 h of optimized Efavirenz-NLCs. A 10-fold increment in % DTE (drug transport efficiency) and 4.5-fold increment in % DTP (drug transport percentage) for the optimized formulation was found in comparison with free Efavirenz. From subacute 28-day intranasal toxicity study, it was found that there was no toxicity caused by encapsulated Efavirenz in experimental animals over the free drug. Therefore, NLCs could be a promising nanocarrier for brain delivery and also in the controlling of neuroAIDS [87].

Nanoemulsions
Nanoemulsions are oil, water, surfactant, and co-surfactant containing colloidal dispersions with size ranging from 20 to 500 nm [88]. Owing to their properties of good optical clarity, rapid digestibility, sustained release, drug targeting, and reduced toxicity, Nanoemulsion (NE) has emerged as a potential drug delivery approach [89,90]. Limited bioavailability of lipophilic drug molecules can be taken care of by loading the drug in the oil phase of O/W NE. This further improves the absorption of the lipophilic drugs by favouring their solubilization [90]. Owing to the liquid nature of nanodroplet core, NE has been privileged with high drug loading capacity for lipophilic drug particles. Other than various transport systems already mentioned in "Polymeric nanoparticles," NE promotes the delivery of lipophilic drug molecules by lipid exchange through the fusion of the oily phase and surfactant layer with BMEC, i.e., brain microvessel endothelial cells [91]. Also, an appropriate selection of surfactants possessing P-gp efflux inhibiting activity can be exploited to enhance the bioavailability by circumventing the portal circulation [89]. Table 2 contains data of some previous year's research work for ARV-loaded nanoformulations fulfilling the objective of targeting viral reservoirs in the brain.
Karami and associates developed lactoferrin treated indinavir-loaded nanoemulsions (Lf-IDV-NEs) for promoting drug delivery to the brain. In vitro studies revealed an initial burst release followed by a gradually increasing release rate with 80% of cumulative drug release from IDV-NEs. As per in vivo studies, an approx fivefold higher drug concentration was found in the brain from Lf-treated IDV-NEs than with free drugs. The brain concentration-time curve values for AUC 0-4 h showed an increment of 4.1-folds with Lf-IDV-NEs and 1.6-folds with IDN-NEs when compared with free drug. The parenchymal uptake clearance was enhanced by 393 and 420 times for IDV-NEs and Lf-IDV-NEs, respectively, versus free IDV justifying a more prolonged residence time in the brain due to the abundance of Lf receptors on brain parenchyma. Thus, it was concluded that a superior brain targeting was achieved with both lactoferrin-treated and non-treated nanoemulsions as compared with the free drug along with a prolonged drug stay in the brain [92].
Desai and Thakkar depicted an enhanced oral bioavailability and a superior brain uptake of Darunavir by loading it in a lipidic NE. The optimized formulation depicted a high entrapment efficiency of 93%. The C max and AUC values were found to be increased by almost double and more than double respectively for NE when compared with the plain drug suspension. In vitro studies resulted in 76% drug release from NE with respect to only 11.50% release from plain drug suspension after 8 h. Improved endocytosis and transcytosis indicated a higher brain uptake of Darunavir from the lipidic formulation than suspension. Thus, formulating the drug into NE improved bioavailability and brain targeting and lessened the dose, thereby preventing side effects [89].
The author critically analysed the potential role of NE in improving both in vitro and in vivo pharmacokinetics of drug particles. Oral administration of ARVs as NE greatly improved the bioavailability. NE are prospective candidates as a non-invasive drug delivery system.

Nanocrystalline diamond or "nanodiamond"
Characterized by a very small size ranging from 1 to 100 nm, Nanodiamond (ND) emerged out as a new class of nanoparticles in the carbon family [100]. ND is a crystalline carbon particle demonstrating a unique property to allow surface modifications by the addition of various chemical functional groups. ND functions as a non-toxic, biocompatible, and chemically inert nanocarrier [101]. It can be depicted as a nanosystem bearing a core-shell arrangement with an inert diamond carbon core and a graphite-based shell [100]. The surface electrostatic potential of ND draws the water molecules to the surface leading to increased solubilization and better adsorption of hydrophobic drug molecules. Therefore, antiretroviral agents that are not stable or dispersible in water can be delivered effectively through ND [101]. Owing to its small size and negligible toxicity potential, ND can be explored as an ideal opportunity for improving drug delivery to the CNS.
Roy and associates aimed to characterize unmodified and surface-modified (-COOH and -NH2) efavirenz-loaded ND for their ability to target the brain. The in vitro dissolution data depicted a sustained release profile of efavirenz from unmodified ND formulation when compared with free drug demonstrating superior pharmacokinetic characteristics of ND-EFV in vitro. This sustained pattern allowed for consistent drug delivery to viral CNS reservoirs. ND-EFV depicted a significantly slower release profile and prolonged retention time of EFV in CNS. Figure 3 shows decreased p24 levels which further confirmed the therapeutic efficacy of the EFV-loaded ND in HIV-1 infected macrophages. Thus, ND-based delivery proved out to be non-toxic to the brain and also depicted enhanced transmigration across BBB [102].

Vesicle-based drug carriers: liposomes and niosomes
Vesicular systems are known to encapsulate and protect the pharmaceutical agents which are susceptible to degradation, thereby increasing the effective drug lifetime and enhancing therapeutic outcomes by targeting specific tissue types. Vesicle-based carriers guard the encapsulated drugs in the varying pH of the gastrointestinal tract allowing an effective oral delivery. They are capable of enhancing the rate of transdermal transport of the drug when applied topically. Also, this nanocarrier system shows a reduced drug clearance and an extended circulation time on administrating intravenously [103]. The vesicular system has emerged as a promising approach for brain-targeted drug delivery as discussed briefly in the following sections. A large number Indinavir loaded lipidic NEs intended for i.v. administration was found stable after the sterilization process. Fluorescent dye studies depicted an improved brain uptake of indinavir. PK studies revealed higher drug levels in brain tissue (~ 2.5 times) from Tween-80 containing indinavir NE as compared with plain drug solution. A higher brain-to-plasma ratio (1-threefold) subsequent to i.v. NE dose indicated a successful brain-targeted delivery in depleting viral loads in HIV infection [99] of antiretroviral drugs have been formulated as vesicular drug carriers. However, their potential in targeting the CNS viral reservoirs is still lagging.

Niosomes
Niosomes are the non-ionic surfactant-containing vesicles. Bearing a bilayer structure, niosomes are formed by the selfassociation of non-ionic surfactants in the aqueous phase. The amphiphilic nature of the non-ionic surfactants provides it with an ability to load both hydrophilic and lipophilic drug moieties. Also, the non-toxic, less hemolytic, and non-irritating nature of non-ionic surfactants makes them an ideal excipient as compared with other cationic and anionic surfactants. These surface modified niosomes exhibit active targeting of BBB by binding to certain receptors (viz., transferrin, insulin, low-density lipoprotein (LDL)) present on the brain [104]. Niosomes promote successful delivery of drugs by reducing the clearance rate, targeting the specific site, and by protecting the encapsulated drug. Targeting of the drug to a specific site using niosome reduces the doserelated side effects [105]. Santha Sheela and associates developed optimized emtricitabine-loaded n-palmitoyl glucosamine (NPG) niosomes for brain-targeted drug delivery. Considering the property of high cerebral glucose uptake, niosomes functionalized with glucose analogue were explored. Formulations containing Span 60 and Span 40 were evaluated for various formulation parameters. The mean particle size of the formulation containing Span 40 was significantly greater than that of Span 60, whereas drug encapsulation was found to be approximately 3 folds higher with Span 60. NPG niosomes were found to be stable for 6 months under 4 °C and 25 °C. it was concluded that NPG niosomal preparation containing Span 60 in optimized concentrations was considered as a prospective substitute to improve brain-targeted delivery of emtricitabine thereby, lessening related HIV-associated neurocognitive disorders [105]. The authors here critically analysed the significance of the functionalization of niosomes towards improving their penetration into the brain. Also, the success of using Span 60 over Span 40 establishes that longer chains of Span 60 (C18) possess a capability for higher drug entrapment than Span 40 (C16).

Liposomes
Liposomes are the nanosized vesicles that are composed of an aqueous core surrounded by one or more lipid bilayers. Liposomes are capable of accommodating both hydrophilic and hydrophobic therapeutic agents. The surface of the liposome can be tailored by the inclusion of certain macromolecules including antibodies, aptamers, proteins, and peptides which further promotes active targeting to the brain as depicted in Fig. 4. Strategies involving cationization of the carrier, surface-functionalization of liposomes, and development of stimuli-responsive liposomes have been explored for enabling the delivery of therapeutics across the BBB. Owing to their biocompatible and biodegradable nature, liposomes have been considered suitable to be employed for neuro medicines [106].
Jayant and associates developed novel magneto-liposomal nanoformulation (NF) and evaluated for in vitro and in vivo BBB transmigration and their antiviral efficacy. PEGylated magneto-liposomal NF was developed and characterized for various parameters viz., size, shape, drug loading, and in vitro BBB transportation ability. The studies revealed a sustained release of drug for up to 10 days. The NF was able to decrease the HIV-1 infection up to ~ 40-50% in vitro. The provided magnetic treatment of approximately 0.8 T was able to transport NF effectively without inducing any toxic effects in the brain as well as maintain the integrity of BBB. The in vitro cytotoxicity studies depicted that treatments with different concentrations of NF did not mark any evidence of cytotoxicity as depicted by a similar percentage of viable cell population with that of the untreated group in Fig. 5. Thereby, the developed NF can be considered as a safe and a better approach for treating HIV-1 infection and to eradicate HIV-1 brain reservoirs [107].
Tomitaka and associates developed hybr id multifunctional magneto-plasmonic liposomes (MPLs) by co-encapsulating magnetic nanoparticles (MNPs) and anti-HIV drug, tenofovir disoproxil fumarate (TDF) into dipalmitoyl phosphatidylcholine (DPPC) liposomes. The cytotoxicity studies revealed that exposure to MPLs up to the concentration of 10 μg MNP/ml marked no significant decrease in the viability of the primary human astrocytes within 48 h. Transendothelial electric resistance (TEER) of the in vitro BBB model indicates that the transmigration of liposomes in the presence of a magnetic field gradient did not disrupt BBB integrity. Encapsulation of TDF into liposomes facilitated effective cellular uptake inside the infected microglial cells enabling an efficient inhibition of viral replication against neuroAIDS [108].

Extracellular vesicles
Extracellular vesicle (EV) is the phospholipid membranebound vesicles that have gained much recognition in recent times [109]. EV with a size ranging from 20 to 1000 nm is a hypernym categorized into exosome, microvesicles, and apoptotic bodies and is released allover by various cells [110]. EV can hold nucleic acids, proteins, lipids, carbohydrates, and hormones and helps Fig. 4 Surface functionalized liposomal formulation by covalent interaction with (i) antibody, (ii) aptamers, (iii) proteins and (iv) peptides with their receptor sites along neurons, and (v) Liposomal uptake by brain following adsorptivemediated endocytosis (AME) by electrostatic interaction between cationic moiety and negatively charged sites on blood capillaries in the cell-to-cell transmission of the same. Earlier considered as a mere excretory product of various bodily fluids, EV is now being highly explored for its role as a biomarker in disease diagnosis, an agent for cell-cell signalling, a modulator in various immunological and inflammatory reactions, and cancer progression. The ability of this membrane-bound vesicle for surface functionalization makes it eligible for targeting sitespecific receptors, thereby rendering it with a property of targeted release action [111]. Due to its endogenous origin, EV acquires the privilege of being biocompatible, immune-compatible, and least toxic to the host body [110]. Though the mechanism of traversing across the BBB is not clear, EV appears to be taken up through various endocytotic pathways (receptor-mediated endocytosis, clathrin-independent endocytosis) and macropinocytosis [110,112]. Also, an extended circulation of EV by the virtue of its ability to escape the macrophage-mediated digestion and phagocytosis makes it a favourable choice for clinical use [109].
Though EVs released from the infected cells containing HIV factors contributes towards worsening of NeuroAIDS, some exosomes secreted by the T cells and the astroglial cells have a potential for inhibiting transcription of HIV-1. Barclay and associates investigated the effects of exosomes released from the uninfected HIV cells on the latent HIV cells present in the brain. It was concluded from their study that the exosomes from uninfected cells triggered an increased production of HIV transcripts from the neighbouring latent HIV cells. This may be possibly due to an enhanced loading of RNA Polymerase II via exosomes on the infected cells. Thereby, causing the latent HIV to rejuvenate and making them susceptible to the c-ART [113]. According to the authors, due to the property of shuttling various factors, EVs have a great potential to help eradicate the HIV latent reserves in NeuroAIDS. However, extensive research is a pre-requisite in the development of EV as a successful drug delivery system.

Metal-based nanoparticles
Metal nanoparticles (NPs) are ranging from 1 to 200 nm in their size, and depending on their size and shape, they exhibit remarkable physicochemical characteristics [114].
Various types of metal-NPs are there, but the most widely studied are gold, silver, copper, and iron, although other metal-NPs are also existed such as selenium, gadolinium, palladium, titanium oxide, zinc-oxide, and cerium-dioxide for drug delivery.
Metal-NPs have distinct advantages like gold, and silver NPs have surface-plasmon-resonance (SPR), whereas dendrimers, micelles, and liposomes do not have these characteristics. Many other advantages are demonstrated by metal-NPs such as good biocompatibility and versatility when it comes to surface-functionalization. Additionally, the alteration and functionalization of these NPs with particular functional groups enable them to bind with drugs, antibodies, and other ligands, so that they can be more promising in biomedical applications [115]. The major mechanisms for metal-NPs delivery to the CNS are adsorptive-mediatedtranscytosis (AMT), receptor-mediated-transcytosis (RMT), but not the carrier-mediated-transport (CMT), which is mainly for small molecules. AMT depends on the interaction of the cationic compounds or charge which is present on a metal-NPs with negative charges present on the plasma-membrane (sulfatedproteo-glycans), directing to an endocytosis pathway independent of membrane receptors which influence the transcytosis. In the AMT mechanism, there is a lack of selectivity which is the main limitation of this BBB crossing pathway. As compared with AMT, RMT is a highly selective pathway that consists of receptor-ligands recognition at the luminal side of BBB, followed by exocytosis at the abluminal side. RMT has been broadly studied for the delivery of large molecules, polymericcomplexes, liposomes, and NPs across the BBB [116].
Research conducted by Borker and associates fabricated pectin reduced gold nanoparticles (PEC-AuNPs) as a carrier for delivery of zidovudine (AZT) to macrophages. In vitro study revealed the sustained release of AZT from AuNPs-complex in an acidic environment which demonstrates beneficial as the drug will be released in endosome after the uptake by RMT in target cells. In vitro cytotoxicity study revealed a reduction in cytotoxicity of AZT-loaded PEC-AuNPs as compared with AZT-solution. In vivo study showed an increment in the amount of AuNPs due to favoured uptake of PEC-AuNPs by macrophages. Thus, PEC-AuNPs can be a promising nanocarrier for targeting viral-reservoir sites [117].

Nano vaccine
Vaccination/immunization is the method of imparting a stimulus to the immune system of humans to fight against specific diseases. Due to the arising safety concerns and eliciting a weaker immune response, the development of nano vaccines has emerged as a promising alternative to conventional vaccination [32]. Nano vaccines are nanoparticle vaccines with a size ranging from 20 to 100 nm. The ability of nano vaccines to conjugate with various antigens and adjuvants has been shown to enhance the efficacy of the vaccine along with an altered in vivo immune response [118]. Owing to its small size and the potential for surface modifications, nano vaccines enable targeted delivery of antigens for triggering a superior immune reaction [32,119]. Also, the ability of nano vaccines to protect proteolytic degradation as well as encouraging uptake of antigens by the antigen-presenting cells (APC) has made this area quite interesting for research [120].
Dubrovskaya and associates carried out vaccination to elicit CD4 binding site-directed, cross-neutralizing antibodies via Glycan-Modified HIV NFL Envelope Trimer-Liposomes. The experiment was performed to provide immunization with HIV neutralization. The outcomes depicted a successful elicitation of broadly neutralizing antibodies (bNAbs) along with 87% HIV neutralization breadth [121].
Though a good number of nano vaccines have been developed for various viral diseases and cancer therapy, the nano vaccines for combating NeuroAIDS are in the development arm. As per the critical analysis of the author, nano vaccines for targeting brain reserves of HIV need extensive research.

Clinical study data
Numerous nano-based therapeutic systems for antiviral drugs have entered into clinical practice and are being investigated under different phases of clinical studies. Through extensive clinical data is not available for the nanoforms under antiretrovirals, some of the studies have been described as given [122]. The results of the following clinical studies have been tabulated below in Table 3.
An interventional Phase I study has been carried out for Doravirine (MK-1439) formulated as solid drug nanoparticles to evaluate and compare the relative bioavailability of different MK-1439 experimental nanoformulations (NFs) with that of an MK-1439 filmcoated tablet for the treating HIV-1. The study was a single group assignment, open-label, and incorporated 16 participants. Primary and secondary outcomes including various bioavailability parameters and incidences of adverse reactions were noted [123].
DermaVir patch (LC002) is a novel HIV therapeutic vaccine containing a DNA plasmid that codes for most of HIV-1's proteins. DermaVir is a synthetic pathogen-like nanomedicine. DermaVir is targeted to Langerhans cells by topical administration which then migrates to lymph Phase I The outcomes complied with the protocol sufficiently to ensure that the data exhibited the effects of treatment. Also, 0.00% of mortality and 0.00% of serious adverse events were observed [123] A phase ii randomized, placebo-controlled, multi-centre study to evaluate the safety, tolerability, immunogenicity, and antiretroviral activity of dermavir patch (LC002) in treatment-naïve HIV- Phase I A suppression of HIV-RNA in patients on cART over the previous 6 months. All doses of DermaVir immunization were safe and well-tolerated. There was no death, no serious adverse event, and no discontinuation from the study [127] nodes and induces HIV-specific T cells that can kill HIVinfected cells. DermaVir nanomedicine was administered topically using the DermaPrep device. A phase II randomized, placebo-controlled, dose-finding, doubleblinded, multicenter study was performed to assess the safety, tolerability, immunogenicity, and preliminary antiretroviral activity of DermaVir patch (LC002) in adults with HIV-infection. Primary and secondary outcomes included the safety endpoint studies, CD8+ and CD4+ T cell count, and the HIV-specific memory T cell responses (repeated dermavir immunizations in HIV-1 infected treatment-naïve patients). The actual study was completed on January 1, 2015. However, no results have been posted for the same [124]. Another interventional clinical study was conducted to study the Safety, Tolerability, and Immune Response to LC002, an experimental therapeutic vaccine, in adults receiving HAART for treating HIV infection. LC002 is a novel HIV therapeutic vaccine containing a DNA plasmid that codes for most of HIV-1's proteins. The study involved three cohorts. Phase I and II studies were completed in 2010 [ [125], 126].
The GIHU004 phase I trial was designed to evaluate the safety, tolerability, and immunogenicity of DermaVir immunotherapy in individuals with chronic HIV-1 infection treated with fully suppressive cART. DermaVir nanomedicine was administered topically using the DermaPrep device. This Phase I study enrolled nine HIVinfected adult subjects. [127].

Future perspectives
Nanotherapeutics have been emerged as a safe and effective drug delivery approach to eradicate viral load from the reservoir sites which are not achievable by the free drugs in adequate concentrations. Nanotherapeutics provides a remarkable improvement in the ability to enhance drugtranslocation across the BBB. The development of multifunctional drug-loaded-nanotherapeutics having the permeability to cross the BBB will offer progress towards the therapy of neuro-AIDS. Different unconventional drug delivery systems such as nano-bubbles, nano-robots, nanofibres, nano-traps, and nano-diamonds have widened our vision and extend a whole new area of research in the direction of antiretroviral therapeutics; therefore, nanobased drug delivery systems have a leading role to play in nano-medicine in future. Further investigation must be done for the safety and efficacy of the antiretroviralnanotherapeutics. At last, scale-up considerations for the fabrication of nanotherapeutics are another problem that needs to be addressed to make the nano-based drug delivery system approach useful.

Conclusion
The review consists of the novel nanotherapeutic drug delivery strategies for efficient delivery of antiretroviral drugs to the brain to eradicate the HIV reservoirs. Numerous efforts have been made to make the drugs bioavailable by formulating them into various nanoforms. Solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanocarriers, nanoemulsions, nanodiamonds, vesicle-based drug carriers, metal-based nanoparticles, and nano vaccines have been reported for their role in successful drug delivery to the brain. The challenges with the conventional delivery of antiretroviral therapy can be overcome by employing nanocarriers.