Tumor Acidity-Activatable Ionizable Lipid Nanoparticles for Selective Oncolytic Therapy.

Ionizable lipids, widely employed as pharmaceutical excipients for gene delivery, exhibit acidity-responsive membrane-destabilizing activity. This property prompted us to hypothesize that such membrane-destabilizing activity could be harnessed and selectively confined to the acidic tumor microenvironment (aTME) to achieve tumor-selective oncolysis. Herein, we report the rational design of tumor acidity-activatable oncolytic lipid nanoparticles (aoLNPs) through programmed structural modulation of ionizable lipids. By designing and screening an ionizable lipid library with systematic variations in alkyl tail length and number, we found a clear correlation between the total tail carbon number and the pH-dependent cytotoxicity of the corresponding lipid nanoparticles. Subsequent library expansion led to the identification of aoLNPE14A6-2 as the optimal candidate, which exhibited selective cytotoxicity toward cancer cells at pH 6.8 and demonstrated potent antitumor efficacy in vivo. Mechanistic investigations revealed that aoLNPE14A6-2 selectively induces lysosomal vacuolation and endoplasmic reticulum stress under tumor acidic conditions, ultimately leading to plasma membrane rupture. Notably, aoLNPE14A6-2 did not cause obvious chronic toxicity or structural damage to normal tissues after intravenous injection. This study expands the application of ionizable lipids for selective oncolytic therapy.