# Pro‐ATO/Allicin Liposomes for Dual‐Pathway Targeting of p53‐Mutant Tumors

## TL;DR

A new liposomal treatment combines pro-ATO and allicin to target p53-mutant tumors by reactivating p53 and inhibiting DNA repair pathways.

## Contribution

A novel liposomal nanomedicine co-delivers pro-ATO and allicin for dual-pathway targeting of p53-mutant cancers.

## Key findings

- The liposomal formulation improves drug stability, pharmacokinetics, and tumor accumulation.
- The treatment enables selective p53 reactivation and ATR inhibition, inducing synthetic lethality in p53-mutant tumors.

## Abstract

Mutations in the tumor suppressor p53 disrupt DNA damage response (DDR) and drive therapeutic resistance in lung cancer. Although arsenic trioxide (ATO) can restore transcriptional activity of structural p53 mutants, its clinical application is limited by subtype selectivity and systemic toxicity. In parallel, p53 deficiency creates dependence on S/G2 checkpoints, rendering ATR a synthetic lethal target; however, allicin, a natural ATR inhibitor and hydrogen sulfide (H2S) donor, suffers from poor stability and bioavailability. Here, we developed a liposomal nanomedicine co‐delivering pro‐ATO (As5+) and allicin (AsAcP@LP) to integrate mutant p53 reactivation with DDR‐targeted synthetic lethality. This formulation improves drug stability, pharmacokinetics, and tumor accumulation while masking allicin's odor. Upon tumor‐specific release, allicin‐mediated redox activation converts As5+ to cytotoxic As3+, enabling selective p53 reactivation, concurrent ATR inhibition, and H2S‐amplified apoptosis. AsAcP@LP exhibits synergistic antitumor efficacy with favorable tolerability, providing a rational nanotherapeutic strategy for p53‐mutant cancers.

Schematic illustration of the “pro‐ATO”/allicin liposomal strategy. Liposomal encapsulation improves the stability and bioavailability of both agents while masking allicin's odor. Upon release in the tumor microenvironment, ATO reactivates structural p53 mutants, and allicin inhibits ATR signaling while releasing H2S, collectively inducing synthetic lethality. This dual‐action mechanism synergistically integrates p53 reactivation with DNA damage response inhibition, resulting in enhanced antitumor efficacy against p53‐mutant cancers.