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

ABSTRACT 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.