Degradable Metal‐Small Molecule Drug Coordination Nanomedicines for DNA Damage‐Augmented Cancer Chemodynamic Therapy

Abstract The intrinsic DNA damage repair response represents a major limiting factor for the therapeutic efficacy of many anticancer therapies such as chemodynamic therapy (CDT). Here, a degradable metal‐small molecule drug coordination nanomedicine (siAPE1/Cu‐MP@HA) is developed for DNA damage‐augmented CDT treatment of lung cancers. The design is achieved by the coordination‐driven self‐assembly of Cu 2+ and 6‐mercaptopurine (6‐MP) with the siAPE1 loading and hyaluronic acid (HA) modification. The siAPE1/Cu‐MP@HA possesses the tumor targeting ability and is degradable in lysosomes for specific releases of Cu 2+ , siAPE1, and 6‐MP because of the weak acidity/glutathione (GSH) dual‐responsiveness. Upon the depletion of endogenous GSH, the siAPE1/Cu‐MP@HA promotes the ∙OH generation from endogenous H 2 O 2 via the Fenton‐like reaction, significantly enhancing the CDT anticancer effect. It is evidenced that the siAPE1/Cu‐MP@HA treatment effectively disrupts the DNA synthesis and inhibits the DNA damage repair, thereby augmenting the DNA damage. In vivo, experiments demonstrate the remarkable therapeutic efficacy against A549 lung cancer in mice with negligible systemic toxicity after intravenous administration of the siAPE1/Cu‐MP@HA. This study offers an innovative approach targeting the DNA damage repair system for enhancing CDT effects in cancer treatment.