Localized delivery of gel-embedded siRNA nanoparticles for pancreatic cancer treatment: Formulation, biodistribution, and bioactivity in mice

Pancreatic cancer (PC) is one of the most lethal malignancies, primarily due to its dense extracellular matrix and poor vascularization, which limit effective drug accumulation and therapy. Here, we de-scribe a local siRNA delivery system using thermosensitive hydrogel-embedded nanoparticles (NPs). siRNA against VAV1 (siVAV1), a key protein implicated in PC, was encapsulated in poly(lactic-co-glycolic acid) (PLGA)-based NPs decorated with an ApoB-derived peptide as the targeting ligand. The ApoB-targeted NPs exhibited optimal physicochemical properties, including nanoscale size, low poly-dispersity index, and a neutral charge. The sustained-release siRNA-NPs were incorporated into a ther-mosensitive hydrogel (poloxamer) and locally injected into the pancreas of tumor-bearing mice. Treatment with targeted NPs in gel (tNPs@G) resulted in a notable increase in accumulation within the tumor (1.9-fold) and spleen (1.3-fold) 72 hours post-injection, with minimal systemic exposure and no local cytotoxicity. Intra-tumoral implantation of the gel-laden siVAV1 NPs in PC-bearing mice led to a significant reduction in tumor growth and volume (2.6-fold), mediated by the inhibition of both VAV1 mRNA and protein, and improved survival rates. The developed local siRNA delivery system provides a minimally invasive and effective therapeutic approach for PC, addressing key drug delivery barriers.