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

PTEN and p53 are two pivotal tumor suppressor proteins that act synergistically to restrain tumor progression but are frequently inactivated in tumors. Restoration of their tumor suppressor functions holds promise for fundamentally inhibiting tumor growth. However, it is hampered by unsustainable protein production, insufficient intracellular delivery, and off-target side effects. Here, we report a biohybrid therapeutic platform that integrates engineered attenuated Salmonella typhimurium VNP20009 (VNP) with nanotechnology to enable durable restoration of PTEN and p53 functions in tumors. The VNP strain was genetically engineered with a quorum-sensing (QS)-regulated lysis and PTEN-expression system, thereby maintaining bacterial density within a controllable range, markedly improving in vivo safety, and enhancing PTEN release by 5.2-fold. Notably, VNP exhibits intrinsic tumor-targeting capability and long-term intracellular parasitism over 7 days, functioning as an exogenous organelle mimic in tumor cells that enables sustained PTEN delivery and restoration of tumor suppressor activity. Moreover, RG7388-loaded nanoparticles (RG-NPs) were conjugated onto the bacterial surface, allowing efficient intracellular delivery and sustained release of an MDM2 inhibitor to elevate p53 levels and synergize with PTEN-mediated tumor suppression. This biohybrid platform achieved up to 94.9% tumor inhibition in a murine melanoma model and conferred long-term survival in 100% of mice when combined with anti-PD-1 therapy, highlighting its strong therapeutic promise for cancer therapy and the potential of engineering VNP as a programmable exogenous organelle mimic.