Inhibiting NFS1 by Targeting Liposomes for Combating Cisplatin‐Resistant Colorectal Cancer

Abstract Cisplatin (CP) resistance causes clinically negative effects on colorectal cancer (CRC) chemotherapy through various mechanisms. Currently, overcoming CP resistance while minimizing systemic toxicity remains an urgent need in CRC treatment. Combination therapy offers an appealing strategy to mitigate tumor resistance to CP. Targeting inhibition of NFS1 cysteine desulfurase (NFS1) represents an emerging strategy to combat CP resistance in malignancies. Through suppressing NFS1 activity, NFS1 inhibitors (NI) effectively trigger PANoptosis via oxidative stress amplification and synergize with CP to eliminate tumor cells. However, the non‐specific biodistribution of both CP and NI contributes to systemic toxicity. In addition, the different physicochemical properties of CP and NI hinder their synergistic delivery. To address these issues, a D18 peptide‐modified liposome (DLP) is developed for tumor‐targeted co‐delivery of CP and NI. DLP exhibits active CRC targeting capacity in vivo, activating the anti‐tumor immune response via stimulating DCs maturation and CD8 ⁺ T cell infiltration. Furthermore, DLP improves the efficacy of CP chemotherapy and suppresses CP‐resistant CRC growth through upregulated PANoptosis. The targeting liposome provids a promising strategy for clinical transformation of CP‐resistant CRC therapy.