Ionizable Lipid Nanoparticles Activated by Tumor Acidity for Targeted Cancer Therapy

The identified lipid nanoparticle aoLNP_E14A6-2 selectively induces cancer cell death at pH 6.8.

• Ionizable lipids show acidity-responsive activity that can destabilize membranes in acidic environments, like tumors.
• A systematic design of ionizable lipids revealed a correlation between the carbon number in the lipid tails and their cytotoxic effects at different pH levels.
• The optimal lipid nanoparticle candidate, aoLNP_E14A6-2, demonstrated strong effectiveness against cancer cells in acidic conditions.
• aoLNP_E14A6-2 triggers specific cellular responses, including lysosomal vacuolation and endoplasmic reticulum stress, in acidic tumor environments.
• No significant chronic toxicity or damage to normal tissues was observed after intravenous administration of aoLNP_E14A6-2.

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