A Trojan horse nanoplatform overcoming delivery barriers for targeted gene immunotherapy of colorectal cancer

Abstract

Programmed cell death ligand 1 (PD-L1) antibody has been shown to hold tremendous promise in curing metastatic colorectal cancer (CRC). However, the delivery efficacy of the targeted biologics limits this immunotherapy in a subset of CRC. Here we report a novel biomimetic ‘Trojan horse’ nano-delivery system for targeted gene-immunotherapy of colorectal cancer. The system comprises a core of gold nanoparticles and cationic liposomes encapsulating CRISPR/Cas9–sgSOX9, camouflaged with homologous CRC cell membranes for immune evasion and tumor tropism, and functionalized with PD-L1 antibodies to enhance tumor recognition and relieve immune suppression. In vitro , the nano-system potently suppressed CRC cell proliferation, migration and invasion. in vivo , it exhibited robust tumor-targeting specificity, favorable preliminary biosafety profile and marked inhibition of tumor growth in subcutaneous xenograft models. Mechanistically, the system remodeled the tumor microenvironment by promoting CD8 + T-cell infiltration and elevating effector cytokines IFN-γ and TNF-α. By seamlessly coupling precise gene delivery with potent immune activation, this nanoplatform offers a compelling therapeutic strategy for colorectal cancer therapy.