Organ-selective lipid nanoparticles for precise cancer therapy: Beyond liposomes and polymeric micelles

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Regulating the biodistribution of nanoparticle-based drug delivery systems (NDDSs) by tailoring their physicochemical properties for organ-selective drug delivery is a rational strategy for precise therapy of organ-related cancer. Unfortunately, it remains inconclusive and even conflicting as to the correlation between the physicochemical properties of NDDSs and their biodistribution, due to the interplay of the physicochemical properties, high diversity of NDDSs type, and lack of a criteria for biodistribution evaluation. We synthesized lipid nanoparticles (LNPs), liposomes (LPs), and polymeric micelles (PMs), the most successful NDDSs, with different compositions and surface charges, and systematically compared their biodistribution by determining loaded docetaxel (DTX). It was found that LNPs, regardless of composition and surface charge, showed generally improved biodistribution in the liver, spleen, and lung compared with LPs and PMs. Stiffer structure of LNPs than LPs contributed to the improved biodistribution by improving their pharmacokinetics and cell uptake, which was theoretically and experimentally verified. More importantly, results further suggested that lipid composition, especially lipid combination, profoundly impacted the biodistribution of LNPs and accurately tailoring LNPs formulation using commercially available lipids could effectuate selective biodistribution to the lung or liver. In lung- and liver-related tumor models, LNPs exhibited enhanced therapeutic potency, as compared to LPs and PMs, which was further significantly enhanced once endowed with organ selectivity. While LNPs are mainly focused on delivering nucleic acid molecules, this work first unveils therapeutic superiority of LNPs as carrier of chemotherapeutic agents over LPs and PMs, and highlights the potential of organ-selective LNPs in precise cancer therapy.