Galangin Nano‐Cocktail Balances Prodrug Activation and Antitumor Response for Enhanced Cancer Treatment

Abstract Despite potent antitumor activity, the clinical application of SN38 is constrained by undesirable physicochemical properties and a narrow therapeutic window. Prodrug design offers a promising solution, but drug activation delay in tumor cells contributes to unsatisfactory therapeutic outcomes. Herein, it is found that galangin (GA), a natural compound derived from Chinese herbal medicine, evidently enhances the chemosensitivity of SN38 and its prodrug, retaining antitumor activity even at previously ineffective concentrations. It is expected to solve the dilemma of prodrug activation kinetics‐limited antitumor response. Then, a binary nano‐cocktail is fabricated through precise co‐assembly of GA and SN38 prodrug. Rational design of SN38 prodrug significantly reduces its off‐target toxicity. Encouragingly, GA dramatically widens the therapeutic window of SN38, tactfully bridging the gap between prodrug activation and antitumor response. As expected, the nano‐cocktail exhibits potent antitumor activity in both orthotopic breast and colon cancer mouse models. This study advances a unique chemotherapy‐sensitizing regimen with high efficiency and safety toward clinical applicability.