Supramolecular Pretargeting Lipid Nanoparticles Based on Host–Guest Recognition Potentiate Cancer Immunotherapy by Reprogramming Tumor Microenvironment

ABSTRACT 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@cRNA IL‐2F ), enabling intratumoral cytokine production to potentiate antitumor immunity. CN‐LNPs@cRNA IL‐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.