Biodegradable Carbonate Nanogels Loaded with Anti MFAP‐5 siRNA for Anti‐stromal Therapy of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, particularly in advanced stages where therapeutic options are limited. Cancer-associated fibroblasts (CAF) within the tumor microenvironment (TME) contribute significantly to tumor progression and represent a promising therapeutic target. In this study, we developed biocompatible and biodegradable polycarbonate nanogels for the improved lipid-free, CAF-targeted delivery of siRNA against microfibrillar-associated protein 5 (MFAP-5), a pro-angiogenic factor expressed by inflammatory CAF (iCAF). Using a cirrhotic murine HCC model (C-HCC), we demonstrated that intravenously injected anti-MFAP-5-siRNA-loaded nanogels (NG:siMFAP5) silenced the MFAP-5 expression, reduced fibroblast activation, and suppressed tumor growth in a dose-dependent manner. In vivo biodistribution studies revealed preferential uptake of nanogels by CAF, followed by dendritic cells and macrophages. Mechanistically, MFAP-5 was shown to promote angiogenesis via NOTCH/Hes1 signaling in fibroblasts. MFAP-5 expression in human HCC samples and conserved signaling pathways between mice and humans underscore the translational relevance of this target. Our findings highlight the therapeutic potential of CAF-targeted siRNA delivery using polycarbonate-based nanogels to inhibit stromal-driven angiogenesis and tumor progression in HCC.