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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?

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

Houbing Zhang^1,2, Rupei Du^1,2, Zhiyi Luo^1,2

¹School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou 511442, P. R. China.

Journal of the American Chemical Society

|July 7, 2026

Summary

Researchers designed acidity-activatable oncolytic lipid nanoparticles (aoLNPs) that selectively kill cancer cells in the acidic tumor microenvironment. This targeted approach shows potent antitumor efficacy with minimal toxicity to healthy tissues.

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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.