Immunoregulatory Dendritic Lipopeptide Nanoparticles for High-Capacity Cisplatin Delivery and Pancreatic Cancer Chemo-Immunotherapy.

Lipid nanoparticles (LNPs) are promising for cisplatin delivery but are hindered by low drug loading, instability, and poor efficacy. Here, multicarboxyl dendritic lipopeptides were developed to enhance cisplatin loading via platinum coordination and improve tumor targeting. Structure-activity relationship studies identified DG3 as the optimal lipopeptide, enabling high drug-loading LNPs (hDDLN) with good stability and delivery efficiency. Pt/hDDLN showed a superior therapeutic index over conventional liposomes in vitro and in vivo. Combining Pt/hDDLN with the stimulator of interferon genes (STING) agonists synergistically enhanced immunotherapy by promoting cytotoxic T lymphocyte (CTL) infiltration, dendritic cell (DC) maturation, and reducing Regulatory T cell (Treg). Mechanistically, hDDLN activated DCs via the inducible nitric oxide synthase-cyclic guanosine monophosphate-phosphorylated myosin light chain (iNOS-cGMP-pMLC) pathway, boosting pro-inflammatory responses. This coordination-driven strategy advances LNP-based cisplatin delivery for chemo-immunotherapy of malignancies.