A Smart Nanoparticle-Laden and Remote-Controlled Self-Destructive Macrophage for Enhanced Chemo/Chemodynamic Synergistic Therapy

Macrophages are known to penetrate tumor central hypoxic areas and hold great potential in cancer drug delivery. However, it remains a big challenge for current macrophage-based drug delivery systems (MDDSs) to prevent premature drug leakage and sufficiently release the therapeutics in tumor sites. Moreover, these MDDSs would encounter drug resistance and a hypoxic microenvironment in solid tumors, which further compromised their therapeutic efficacy. Herein, by internalizing a smart nanoparticle (doxorubicin (DOX)-loaded mesoporous carbon nanosphere wrapped with MnO 2 shell) into macrophages, a macrophage vehicle (MMDM) is developed for enhanced chemo/chemodynamic synergistic therapy. The resulting MMDM could avoid premature drug leakage-induced cell dysfunction and maximally maintain cell viability. After accumulating in tumor tissues, the MMDM could be destroyed under a near-infrared laser to sufficiently release the nanoparticle out of the carrier macrophages. The released nanoparticle could then decompose H 2 O 2 to generate O 2 in the tumor microenvironment to relieve tumor hypoxia. Meanwhile, the MnO 2 shell of the nanoparticle is reduced to Mn 2+ by intracellular glutathione, triggering the release of DOX and subsequently resulting in an enhanced Mn 2+ -mediated Fenton-like reaction. This study provides an intriguing strategy to macrophage-based delivery systems for enhanced chemo/chemodynamic synergistic therapy.