Combination　immunotherapy　has　shown　promising　potential　for　enhancing　the　objective　response　rate　compared　to　immune　checkpoint　blockade　(ICB)　monotherapy.　However,　combination　therapy　with　multi-drugs　is　limited　by　the　different　properties　of　the　agents　and　inconsistent　synergistic　targeted　delivery.　Herein,　based　on　a　universal　triterpene　template　and　the　anticancer　active　agent　ursolic　acid　(UA),　a　cytomembrane-coated　biomimetic　delivery　nanoplatform　(UR@M)　prepared　by　the　self-assembly　of　a　PD-L1　targeted　CRISPR/Cas9　system　and　UA　was　designed　for　hepatocellular　carcinoma　(HCC)　treatment.　UR@M　showed　enhanced　tumor　accumulation　in　vivo　with　homologous　tumor　targeting,　and　CRISPR　in　the　nanosystem　exhibited　potent　gene-editing　efficiency　of　76.53%　in　vitro　and　62.42%　in　vivo　with　no　off-target　effects.　UA　activated　the　natural　immune　system　through　the　TLR-2-MyD88-TRAF6　pathway,　which　synergistically　enhanced　the　proliferation　of　natural　killer　cells　and　dendritic　cells　and　realized　excellent　immune　cytotoxic　T　cell　infiltration　by　combining　with　the　ICB　of　PD-L1.　The　strategy　of　work　along　both　lines　based　on　innate　immune　and　adaptive　immunity　displayed　a　significant　effect　in　tumor　regression.　Overall,　the　UA-templated　strategy　“killed　three　birds　with　one　stone”　by　establishing　a　self-assembly　nanosystem,　inducing　tumor　cell　death,　and　promoting　synergistic　immunostimulation　for　HCC　treatment.　©　2024