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

Abstract 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 MnO2 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 H2O2 to generate O2 in the tumor microenvironment to relieve tumor hypoxia. Meanwhile, the MnO2 shell of the nanoparticle is reduced to Mn2+ by intracellular glutathione, triggering the release of DOX and subsequently resulting in an enhanced Mn2+-mediated Fenton-like reaction. This study provides an intriguing strategy to macrophage-based delivery systems for enhanced chemo/chemodynamic synergistic therapy.