Nano-bionic bacteria armed adoptive macrophage therapy against bladder cancer

Bladder cancer is a highly malignant tumor with limited treatment options. Although adoptive cell therapy has shown promise in oncology, its efficacy is often constrained by poor intrinsic antitumor activity and a highly immunosuppressive tumor microenvironment. To address these challenges, this study develops a novel living adoptive macrophage therapy armed with nano-bionic bacteria for bladder cancer treatment. Specifically, hollow manganese dioxide (MnO₂) nanoparticles were synthesized, loaded with an adenosine inhibitor, and coated with E. coli membranes. Under mild conditions, these nano-bacterial particles were internalized by macrophages, transforming them into living cell drug factories. Upon accumulation into the bladder, these engineered macrophages actively infiltrated tumor tissues. Lipopolysaccharide (LPS) from the bacterial membrane, along with Mn²⁺ ions, activated the STING pathway in macrophages, promoting and sustaining an M1-like antitumor phenotype. The activated macrophages released pro-inflammatory cytokines, thereby stimulating resident immune cells within the tumor and initiating robust antitumor immunity. Additionally, the macrophages released the adenosine inhibitor while MnO₂ generated oxygen, synergistically counteracting adenosine-mediated immunosuppression. In a subcutaneous tumor model, this nano-bionic bacteria-armed macrophage therapy significantly enhanced the therapeutic outcome against bladder cancer. Mac@ABMn triggered reprogramming of the tumor microenvironment, resulting in enhanced anti-tumor immunity, characterized by increased infiltration of activated CD4⁺ and CD8⁺ T cells without expanding regulatory T cells (Tregs), thereby shifting the milieu toward a potent immunostimulatory state. The immunostimulatory effect is molecularly defined by the cGAS/STING/TBK1/IFN-β signaling axis, and Mac@ABMn demonstrates significant synergistic efficacy when combined with standard immunotherapies like BCG or anti-PD-L1 checkpoint blockade, leading to superior tumor control. Collectively, this study developed a novel therapy regiment, featuring macrophages engineered with bacterial membrane-coated nanoparticles are activated via the STING pathway to sustain an anti-tumor M1 phenotype while simultaneously alleviating hypoxia and scavenging immunosuppressive adenosine.