Bacteria-targeted dual-lock delivery for closed-loop immune modulation in colorectal cancer.

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.