AbstractShort interfering RNA (siRNA) possesses special ability of silencing specific gene. To increase siRNA stability, transportation and its uptake by tumor cells, effective delivery to the appropriate target cells is a major challenge of siRNA-based therapy. In the present study, an effective, safe and biocompatible survivin siRNA encapsulated, GalNAc decorated PEGylated PLGA nanoconjugates (NCs) viz., GalNAc@PEG@siRNA-PLGA were engineered and their synergistic antitumor efficacy was evaluated for targeted delivery in HCC bearing experimental mice. GalNAc@PEG@siRNA-PLGA NCs were characterized for size, bioavailability, toxicity and biocompatibility. Their antitumor potential was evaluated considering gene silencing, apoptosis, histopathology and survival of treated mice. Exceptional accumulation of hepatocytes, reduction in survivin expression and prominent regression in tumor size confirmed the ASGPR-mediated uptake of ligand-anchored NCs and silencing of survivin gene in a targeted manner. Increased DNA fragmentation and potential modulation of caspase-3, Bax and Bcl-2 factors specified the induction of apoptosis that helped in significant inhibition of HCC progression. The potential synchronous and tumor selective delivery of versatile NCs indicated the effective payloads towards the target site, increased apoptosis in cancer cells and improved survival of treated animals.