Polymeric-lipid nanoparticles that leverage cationic helper lipids and the protein corona for lung-targeted delivery of a novel anti-cancer drug

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, highlighting the urgent need for more effective therapeutic strategies. Nanomedicine offers a promising avenue to improve treatment outcomes by enabling localised drug delivery within the lungs. Drawing inspiration from the recent success of mRNA lipid nanoparticles, we developed a novel class of polymeric-lipid nanoparticles (P-LNPs) designed to encapsulate RB-012, an anticancer compound that inhibits 14-3-3 protein function but is rapidly cleared from systemic circulation due to its cationic and amphiphilic properties. RB-012 was co-assembled with the anionic polymer polyacrylic acid (PAA) and various combinations of cholesterol, pegylated, and charged helper lipids to form stable P-LNPs that significantly impeded in vitro premature drug release. This approach resulted in >30-fold increase in bioavailability following intravenous administration (2 mg/kg) to Sprague-Dawley rats. Varying the helper lipid composition, through the inclusion of 16-32 mol% of the cationic lipid, DOTAP, yielded a > 50-fold increase in pulmonary drug exposure compared to unformulated RB-012. These biodistribution enhancements were linked to altered protein corona profiles on the nanoparticle surface, with P-LNPs formulated with DOTAP increasing the degree of protein corona adsorption in a concentration-dependent manner, compared to P-LNPs prepared with the anionic helper lipid, DOPE. In vitro and in ovo assays confirmed that the P-LNPs significantly improved the anti-tumour efficacy of RB-012, supporting their potential as a targeted therapeutic platform for lung cancer treatment.