A self-driven probiotic nanosystem reshapes extracellular matrix by knockdown of DDR1 for enhanced tumor immunotherapy

Abstract

Immunotherapy represents a promising therapeutic approach for tumor suppression, yet its efficacy is significantly limited by the immunosuppressive extracellular matrix (ECM) characteristic of solid tumors. To achieve simultaneous ECM remodeling and immune activation within a single system, we have developed a self-driven probiotic nanosystem (PL@LDH-CB) based on the probiotic Clostridium butyricum (CB), which incorporates a plasmid-loaded layered double hydroxide (PL@LDH) gene-editing module. Following intravenous administration, the PL@LDH-CB system actively targets tumor sites by leveraging CB’s natural tropism toward hypoxic conditions, thereby efficiently delivering the PL@LDH gene-editing module for ECM reshaping. Within tumors, CB and its metabolites significantly enhance anti-cancer immune responses. Concurrently, the released PL@LDH enables stable nuclear expression of CRISPR-Cas9, precisely knocking down Ddr1 -a gene encoding discoidin domain receptor 1 (DDR1) that mediates immune exclusion through promoting collagen fibrillogenesis and fiber alignment. The depletion of DDR1 ultimately reduces intratumoral solid stress (a compressive force exerted by collagen fibers), leading to comprehensive ECM remodeling. This process markedly improves the infiltration of activated T cells within tumors, thereby significantly enhancing immunotherapeutic outcomes.