Functionalized albumin-based dual-delivery system potentiates chemoimmunotherapy via differential targeting.

The therapeutic efficacy of tumor chemoimmunotherapy is frequently compromised by inefficient drug delivery and the persistence of an immunosuppressive tumor microenvironment (TME). To address these challenges, we engineered a functionalized albumin-based dual-delivery system characterized by a distinct division of labor, orchestrating chemoimmunotherapy via a differential targeting strategy. Specifically, anisic acid-modified human serum albumin nanoparticles loaded with the chemotherapeutic agent pirarubicin (T@AH) were engineered to precisely target tumor cells, eliciting potent cytotoxicity. Concurrently, biotin-modified human serum albumin nanoparticles encapsulating the immunomodulator resiquimod (R@BH) were tailored to accumulate in tumor tissues and selectively target M2-like tumor-associated macrophages (TAMs) via dual-targeting properties, driving their repolarization toward the M1 phenotype. In tumor-bearing mouse models, this strategy significantly suppressed tumor growth and prolonged median survival, demonstrating robust antitumor efficacy. Mechanistically, the immunogenic cell death induced by T@AH synergized with the immune remodeling driven by R@BH to establish a robust chemo-immune positive feedback loop. Functioning as an in situ tumor vaccine, this strategy promoted dendritic cell maturation, enhanced T cell infiltration and activation, induced the polarization of TAMs toward the M1 phenotype, reduced regulatory T cell proportions, and facilitated the release of multiple effector molecules, thereby systematically reversing the immunosuppressive TME. Collectively, this functionalized albumin-based dual-delivery system achieves a dual breakthrough in enhancing delivery efficiency and remodeling the immune microenvironment via differential targeting, providing a promising strategy for highly efficient and synergistic chemoimmunotherapy.