Pro‐ATO/Allicin Liposomes for Dual‐Pathway Targeting of 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 (H 2 S) donor, suffers from poor stability and bioavailability. Here, we developed a liposomal nanomedicine co‐delivering pro‐ATO (As 5+ ) 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 As 5+ to cytotoxic As 3+ , enabling selective p53 reactivation, concurrent ATR inhibition, and H 2 S‐amplified apoptosis. AsAcP@LP exhibits synergistic antitumor efficacy with favorable tolerability, providing a rational nanotherapeutic strategy for p53‐mutant cancers.