Abstract

Clinical evidence reveals that Fusobacterium nucleatum ( F. nucleatum ) colonization and stromal barriers synergistically suppress T cell infiltration, limiting the efficacy of colorectal cancer (CRC) immunotherapy and highlighting the need for a closed-loop strategy to restore antitumor immunity. Here, we present a bio-responsive co -assembled polymeric micelles (CPM-GalNAc) for targeted co-delivery of calcipotriol (Cal) and ornidazole (ONZ), designed to achieve closed-loop immune modulation by simultaneously remodeling the extracellular matrix (ECM) and eradicating intratumor bacteria. Notably, Cal and ONZ were covalently linked via disulfide bonds to form a conjugate (Cal-ONZ), which significantly improved drug encapsulation efficiency compared to individual drug loading. This system employs a dual-lock design: poly(β-amino ester) hydrophobic microdomains undergo hydrophilic-hydrophobic transition in the mildly acidic tumor microenvironment, exposing GalNAc moieties for specific recognition of F. nucleatum . Elevated glutathione levels trigger selective release of ONZ and Cal, where ONZ eliminates F. nucleatum to enhance cytotoxic T cell recruitment through pathogen-associated molecular patterns, while Cal concurrently suppresses cancer-associated fibroblasts and disrupts the ECM, thereby facilitating deeper T cell infiltration. This approach robustly enhances antitumor immune responses, augments the efficacy of αPD-L1 checkpoint blockade, and establishes durable immune memory to prevent recurrence, offering a promising strategy for reinforced CRC immunotherapy.