Engineered bacteria as exogenous organelle mimics restore PTEN and p53 tumor suppressor functions for cancer therapy

PTEN and p53 are two pivotal tumor suppressors that synergistically restrain tumor progression but are frequently inactivated in cancer. Restoring their functions is a promising therapeutic strategy but remains limited by unsustainable protein production and off-target effects. Here, we report a biohybrid platform integrating engineered attenuated Salmonella typhimurium VNP20009 with nanotechnology to enable durable restoration of PTEN and p53 functions in tumors. The bacteria are engineered with a quorum-sensing-regulated lysis circuit coupled to PTEN expression, enabling controlled proliferation and sustained PTEN production and release. Their intrinsic tumor tropism and long-term intracellular parasitism allow them to function as exogenous organelle mimics, providing continuous PTEN supplementation. Surface-conjugated nanoparticles further deliver the MDM2 inhibitor to stabilize p53 and synergistically restore the PTEN-p53 network. This platform achieves 94.9% tumor inhibition in murine melanoma and confers durable survival in all treated mice when combined with anti-PD-1 therapy, highlighting its strong therapeutic potential for cancer treatment. PTEN and p53 are two of the most frequently mutated or inactivated tumor suppressor genes. Here, the authors engineer Salmonella to act as exogenous organelle-like devices that deliver PTEN and an MDM2 inhibitor to reactivate p53 to tumors, achieving durable tumor suppression and synergistic immune activation.