Lipid nanoparticles (LNPs) have emerged as a promising platform for gene/drug delivery in cancer therapy, however their nonspecific biodistribution and extensive hepatosplenic sequestration result in insufficient intratumoral accumulation, thereby undermining the therapeutic efficacy. Here, we establish a sequential pretargeting strategy exploiting the high-affinity host-guest recognition between adamantane (ADA) and cucurbit[7]uril (CB[7]) to enhance tumor enrichment. Preadministered ADA-conjugated anti-PD-L1 antibody (ADA-αPD-L1) primes tumors for efficient capture of subsequently infused CB[7]-functionalized LNPs (CN-LNPs), improving intratumoral retention and cellular uptake. To concurrently address the immunosuppressive tumor microenvironment, NLG919 is covalently incorporated into the ionizable lipid of CN-LNPs to inhibit IDO-mediated tryptophan catabolism, effectively attenuating regulatory T cell activity while preserving the pretargeting functionality of the nanocarrier. CN-LNPs are employed as a delivery platform to encapsulate a circular RNA encoding IL-2-Fc fusion protein (CN-LNPs@cRNAIL-2F), enabling intratumoral cytokine production to potentiate antitumor immunity. CN-LNPs@cRNAIL-2F elicit robust antitumor immunity to suppress tumor growth and extend survival, establishing a versatile platform that overcomes the intratumoral delivery limitations commonly associated with conventional LNPs system.
