Targeted Reprogramming of Vitamin B₃ Metabolism as a Nanotherapeutic Strategy towards Chemoresistant Cancers

Abstract Cancer‐associated fibroblasts (CAFs) promote cancer stem cell (CSC)‐mediated chemoresistance and immunosuppressive tumor microenvironment. However, direct depletion of CAFs may increase cancer invasiveness and metastasis. As a generalized strategy against chemoresistant cancers, Gemini‐like homotypic targeting nanoparticles (NPs) are designed for two‐pronged CAF transformation and cancer cell elimination. The CAF‐targeted NPs couple vitamin B₃ metabolic reprogramming to epigenetic modulation of secreted pro‐stemness and immunosuppressive factors, thereby diminishing CSC and suppressive immune cell populations to enhance cancer cell drug susceptibility and cytotoxic T cell infiltration. In mouse models of breast, liver, pancreatic and colorectal cancers that are resistant to their respective first‐line chemotherapeutics, a single dose of hydrogel co‐delivering the Gemini‐like NPs can rehabilitate chemosensitivity, induce immune activation, and achieve tumor regression. Moreover, it stimulates robust T cell memory for long‐term protection against tumor rechallenge. This study thus represents an innovative approach with broad applicability for overcoming cancer chemoresistance.