Tumor-targeted hybrid micelles enable ROS-responsive CO release and synergistic chemo–gas antitumor therapy

Combination therapy holds great promise for enhancing antitumor efficacy by achieving tumor-targeted and sequentially synergistic cytotoxicity. We developed a tumor-targeted hybrid micellar nanoplatform that co-delivers the chemotherapeutic agent pemetrexed (PEM) and carbon monoxide (CO) for synergistic chemo-gas therapy. PEM and Fe₃(CO)₁₂ were covalently conjugated to D-α-tocopheryl polyethylene glycol succinate (TPGS), yielding two amphiphilic prodrugs—TPGS-PEM and TPGS-CO—which were co-assembled into hybrid micelles. The presence of PEM enabled folate receptor-mediated active targeting, resulting in efficient uptake by 4T1 breast cancer cells. Intracellular esterase-catalyzed cleavage of the ester bond released PEM, which elevated reactive oxygen species (ROS) levels. The increase in ROS triggered site-specific CO release from the Fe–CO complex. This sequential mechanism enabled a cascade of tumor-selective chemotherapy and gas therapy, leading to enhanced apoptosis and reduced tumor proliferation. The hybrid micelles exhibited superior tumor suppression, reduced systemic toxicity, and prolonged survival in tumor-bearing mice.