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

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Abstract
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.
Funding Information
  • National Natural Science Foundation of China (32370096 and 82003622)
  • Taishan Scholar Foundation of Shandong Province (tsqn202312092 and tsqn202312041)
  • Natural Science Foundation of Shandong Province (2023HWQY-068)

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