Targeted Drug Delivery Using Lipid Nanoparticles for Solid Tumor Therapy

Abstract

Lipid nanoparticles -- conventional and PEGylated liposomes, solid lipid nanoparticles, nanostructured lipid carriers, and, more recently, ionizable-lipid nanoparticles engineered for nucleic acid cargo -- have been developed over four decades as vehicles for improving the therapeutic index of solid tumor drug delivery. This article synthesizes that literature around five themes: the formulation chemistry distinguishing the major lipid nanoparticle platforms; passive tumor targeting via the enhanced permeability and retention (EPR) effect and the substantial evidence that has complicated its reliability across human tumors; active targeting strategies that improve cellular uptake after passive extravasation rather than substituting for it; the clinical translation record, from PEGylated liposomal doxorubicin's reduced cardiotoxicity to nanoliposomal irinotecan's statistically significant survival benefit in metastatic pancreatic cancer; and the newer extension of ionizable-lipid nanoparticles into nucleic acid and personalized cancer vaccine delivery. Read together, the literature supports lipid nanoparticles as a genuinely useful and clinically validated solid tumor therapy platform, while falling short of the tumor-selective delivery mechanism the field's early framing of the EPR effect once implied, leaving tumor penetration, EPR-effect heterogeneity, nanoparticle immunogenicity on repeat dosing, and extrahepatic targeting of nucleic acid payloads as open engineering problems for the next generation of formulations.