Charge-Reversed Lipid Nanoparticles Enable Encapsulation of Pt₂L₄ Nanocages for In vivo Anti-Cancer Treatment.

Inorganic anticancer drugs such as cisplatin remain central to chemotherapy but are limited by poor tumor selectivity, rapid clearance, and off-target toxicity. We recently developed cationic Pt₂L₄ nanocages with 12-fold higher anticancer activity than cisplatin in PC-3M-Pro4 cells in vitro, but their positive charge causes rapid extravasation and renal clearance in vivo. Here, we re-engineer lipid nanoparticles (LNPs) into charge-reversed lipid nanoparticles (revLNPs) capable of efficiently encapsulating cationic Pt₂L₄ nanocages. Pt₂L₄-loaded revLNPs retain high cancer-cell uptake and cytotoxicity in vitro comparable to the free drug. Following intravenous administration, they show prolonged circulation, reduced vessel-wall leakage, and favorable biodistribution in zebrafish embryos. In mice, revLNPs exhibit a 1.7-fold longer plasma half-life than the clinically approved Onpattro LNP formulation while maintaining characteristic liver and spleen tropism. In zebrafish xenografts, a single injection induces substantial tumor regression, reaching 20% in PC-3M-Pro4 and 72% in MDA-MB-231 tumors, and outperforms Lipocisplatin despite a ten-fold lower therapeutic dose. These results establish revLNPs as a broadly applicable delivery platform that overcomes solubility, biodistribution, and pharmacokinetic barriers of cationic inorganic drugs, enabling their effective use in vivo.