Authors
Renzo A Knol, Bochuan Hu, Eduard O Bobylev, Martina Farber, Petrus C M Laan, Thomas J F Kock, Bauke Fontein, Johanna Erbani, Oscar Escalona-Rayo, Seline S Roose, Tom Keijer, Gabriel Forn-Cuní, B Ewa Snaar-Jagalska, Leila Akkari, Joost N H Reek, Alexander Kros, Dennis Aschmann
Published in
Advanced materials (Deerfield Beach, Fla.). Pages e75288. Oct 06, 2026. Epub Oct 06, 2026.
Abstract
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.
PMID:
42839697
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.
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