Dual-drug conjugated ionizable lipids for nucleic acid delivery and multidimensional targeted therapy of brain tumors.

Abstract

Lipid nanoparticles (LNPs) are the leading non-viral platform for nucleic acid delivery, and the structural design of ionizable lipids critically determines their delivery efficiency and therapeutic potential. Here, a dual-functional ionizable lipid was developed by integrating a vinpocetine-derived neurovascular regulatory motif with the chemotherapeutic agent temozolomide (TMZ), enabling the construction of a brain-directed lipid nanoparticle platform termed TVP. Compared with the clinically used MC3-based LNPs, TVP significantly enhanced cerebral blood perfusion and exhibited superior brain accumulation in both healthy mice and orthotopic glioma-bearing mice. In addition to improved brain delivery, TVP promoted selective glioma localization and exerted intrinsic anti-glioma activity, while efficiently supporting nucleic acid cargo delivery. When co-loaded with therapeutic nucleic acids, the TVP system achieved potent inhibition of glioma progression through synergistic neurovascular targeting, chemotherapy, and gene intervention, while maintaining favorable biosafety. These findings establish TVP as a multifunctional brain-directed LNP platform and provide a promising strategy for overcoming delivery barriers in glioma therapy.