Superoxide Anion Radical-Activatable Golgi-targeting Prodrug-Based Albumin Complex for Synergistic Chemo-immunotherapy of Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) poses major treatment difficulties because of its aggressive behavior, the absence of targetable receptors, resistance to chemotherapy, and an immunosuppressive tumor microenvironment (TME) promotes that metastasis. Thus, there is an immediate necessity for creative approaches to conquer the treatment dilemma. The Golgi apparatus, central to processing metastasis- and immune escape-related proteins, emerges as a promising therapeutic target of TNBC. Herein, we report a superoxide anion radical (O₂•⁻)-activatable, Golgi-targeting prodrug-based albumin complex (DOX-ISR@HSA-DSPE), which is formed by loading the rationally designed ISR and the chemotherapeutic drug adriamycin (DOX) with human serum albumin (HSA) and mPEG2000-DSPE as carriers, for synergistic chemo-immunotherapy of TNBC. ISR integrates retinoic acid (RA), indomethacin (IMC), and an O₂•⁻-responsive linker. IMC enables precise Golgi targeting via COX-2 recognition while suppressing prostaglandin E2 (PGE2) biosynthesis to reverse TME immunosuppression and inhibit metastasis. HSA and mPEG2000-DSPE carriers synergistically enhance tumor enrichment of both payloads, minimizing off-target exposure to normal tissues. Upon intratumoral O₂•⁻ activation, ISR releases RA to disrupt Golgi function and IMC to inhibit immunosuppressive pathways. This multifaceted approach concurrently implements chemotherapy and reprograms TME, demonstrating potent anti-tumor and anti-metastatic efficacy against TNBC, providing high translational potential for the comprehensive treatment of immunologically cold tumors.