CO/O2-releasing Bi/Cu-TCPP MOF-on-MOF heterostructure enables physical radiosensitization and radioresistance attenuation

Background Radiotherapy efficacy against solid tumors is severely constrained by intrinsic adaptive resistance mechanisms within the tumor microenvironment, notably heat shock protein (HSP)–mediated proteostasis protection and hypoxia/hypoxia-inducible factor 1α (HIF-1α)–driven metabolic reprogramming, which collectively diminish radiation-induced DNA damage and cell death. Conventional radiosensitizers that solely enhance reactive oxygen species (ROS) generation are insufficient to overcome these adaptive survival pathways, highlighting an urgent need for multifunctional platforms that integrate physical radiosensitization with the modulation of biological resistance mechanisms. Here, we present a Mn(CO) 5 Br-modified Bi/Cu-TCPP MOF-on-MOF nanoplatform designed to concurrently enhance radiation energy deposition and modulate tumor adaptive responses. Results The Bi-rich high- Z components augment X-ray absorption and local energy deposition, while the porphyrinic Cu-TCPP framework and Bi/Cu heterointerface facilitate charge transfer and ROS generation. Importantly, X-ray irradiation triggers localized in situ carbon monoxide (CO) release from the Mn(CO) 5 Br moiety alongside Mn-associated oxygen generation, contributing to hypoxia alleviation and suppression of HSP70-mediated stress protection and HIF-1α-driven metabolic adaptation. Conclusion This integrated approach of physical dose enhancement and biological resistance reversal offers a promising avenue to improve radiotherapy outcomes, with no obvious short-term systemic abnormalities observed during the experimental period in a murine model of cutaneous malignant melanoma.