Reassembly nanomaterials-mediated engineered bacteria lysis for reshaping immunosuppressive microenvironment

Bacterial therapy represents a promising strategy for reshaping the immunosuppressive microenvironment of "cold" tumors, owing to the inherent tumor-homing and immunomodulatory capabilities of bacteria. Bacteria can be genetically modified to precisely and continuously release immune activators at tumor sites via synchronous lysis circuits or external physical triggers (e.g., photothermal and magnetothermal methods). However, tumor microenvironment (hypoxia and acidity) interferes with gene expression efficiency, and bacterial metabolites (butyric acid and lactic acid) have potential tumor-promoting risks. In this study, we developed bacteria-nanomaterial hybrid systems (IE-PPCs) to achieve stable and controllable delivery of immune factors while enhancing treatment safety. E. coli Nissle 1917 (EcN) was engineered to express IFN-γ and anchored onto PPCs composed of antimicrobial peptides, MMP-cleavable peptides and hydrophilic PEG. Prior to administration, the expression of IFN-γ in IE-PPCs was precisely regulated by IPTG induction. Upon intravenous injection, IE-PPCs selectively colonized the tumor microenvironment, then MMP-responsive PPCs spontaneously transformed into fibrous nanostructures, exposing antimicrobial peptide residues that lyse the bacteria, thereby releasing IFN-γ and bacterial lysates. IFN-γ directly inhibited tumor proliferation, while combined with bacterial lysates induced dendritic cell maturation and promoted M1 macrophage polarization. In 4T1 mouse breast cancer models, IE-PPCs combined with anti-PD-L1 therapy achieved 89.7% anti-tumor rate, and bacterial loads within tumors decreased by 98.9%. The IE-PPCs system provides a breakthrough strategy for reshaping the immunosuppressive microenvironment and offers a reliable and attractive therapeutic option for cancer patients.