Tumor Acidity-Activatable Ionizable Lipid Nanoparticles for Selective Oncolytic Therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Ionizable lipids are key pharmaceutical excipients for gene delivery.
• These lipids possess inherent acidity-responsive membrane-destabilizing properties.

Purpose of the Study:

• To engineer tumor acidity-activatable oncolytic lipid nanoparticles (aoLNPs).
• To leverage the acidic tumor microenvironment (aTME) for selective cancer cell destruction (oncolysis).

Main Methods:

• Systematic structural modulation of ionizable lipids by varying alkyl tail length and number.
• Screening of an ionizable lipid library to identify optimal candidates.
• In vitro and in vivo evaluation of nanoparticle efficacy and toxicity.

Main Results:

• A direct correlation was found between total tail carbon number and pH-dependent cytotoxicity.
• aoLNP_E14A6-2 demonstrated selective cancer cell killing at pH 6.8.
• aoLNP_E14A6-2 induced lysosomal vacuolation and ER stress, leading to plasma membrane rupture in cancer cells.
• Significant antitumor efficacy was observed in vivo with no apparent chronic toxicity to normal tissues.

Conclusions:

• Rational design of ionizable lipids enables the creation of tumor acidity-activatable oncolytic lipid nanoparticles.
• aoLNPs offer a promising strategy for selective oncolytic therapy.
• This approach expands the therapeutic applications of ionizable lipids in cancer treatment.