Small interfering ribonucleic acid (siRNA) based therapeutics have gained substantial attention due to their specific and efficient gene knockdown efficacies in the presence of effective cargo vectors. Nanogels are identified as non-toxic, blood compatible carriers, which are shown to possess high siRNA loading efficacies and show stimuli responsive (controlled) release, hence providing optimum gene knockdown abilities. Carbohydrate-based cationic nanogels are the most studied vectors. In this study, we report the synthesis of degradable, thermo-responsive cationic glyconanogels via the reversible addition-fragmentation chain transfer (RAFT) polymerization approach. To the best of our knowledge, this is the first study which highlights the use of tailor-made thermo-responsive and degradable cationic glyconanogels for siRNA delivery. These cationic glyconanogels are loaded with epidermal growth factor receptor (EGFR) specific siRNA and the complexes are studied for their net size and charge. The cellular uptake of glyconanogel–siRNA complexes is studied in Hela cells in the presence and absence of serum proteins. Finally, gene knockdown efficacies and cell viabilities of the complexes are evaluated in Hela cells at varying w/w ratios. The siRNA loaded cationic glyco-nanogels show effective gene knockdown efficacies in Hela cells in the presence and absence of serum proteins.