A superoxide anion radical-activatable Golgi-targeting prodrug-based albumin complex for synergistic chemo-immunotherapy of triple-negative breast cancer

Triple-negative breast cancer (TNBC) poses major treatment difficulties because of its aggressive behavior, the absence of targetable receptors, and resistance to chemotherapy, and an immunosuppressive tumor microenvironment (TME) promotes 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) for synergistic chemo-immunotherapy of TNBC. This complex is formed by loading a rationally designed prodrug (ISR, a conjugate of indomethacin, superoxide anion-responsive linker, and <i>trans</i>-retinoic acid) and the chemotherapeutic drug adriamycin (DOX) with human serum albumin (HSA) and mPEG₂₀₀₀-DSPE as carriers. ISR integrates <i>trans</i>-retinoic acid (RA), indomethacin (IMC), and an O₂˙^--responsive linker. IMC enables precise Golgi targeting <i>via</i> 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 the TME, demonstrating potent anti-tumor and anti-metastatic efficacy against TNBC, providing high translational potential for the comprehensive treatment of immunologically cold tumors.