A Mesoporous Calcium Peroxide Nanocuboid with High Tumor Accumulation Across Biological Barriers for High Efficacy Tumor Therapy

Abstract The common problem of tumor therapy based on nanoparticles is the limited efficacy due to the blockage of tumor accumulation by biological barriers. To enhance the drug delivery of nanoparticles across biological barriers and augment their tumor accumulation, herein, a mesoporous calcium peroxide nanocuboid (MCPNC) is developed via a facile hydrolysis‐precipitation method, which can be utilized for high efficacy tumor therapy by promoting a positive feedback loop of Fenton reaction. The biodistribution results demonstrate that MCPNC exhibits higher accumulation in various tissues than calcium peroxide nanosphere (CPNS). Ferroheme (FH) and exceedingly small magnetic iron oxide nanoparticle (IO) loaded MCPNC is modified with hyaluronic acid (HA), forming MCPNC‐FH‐IO@HA. Under acidic tumor microenvironment (TME), Fe ^3+/2+ , H ₂ O ₂ and Ca ²⁺ can be released from MCPNC‐FH‐IO@HA. The reactive oxygen species (ROS) generation through Fenton reaction can disrupt mitochondrial membranes, which accelerates the unbalance of Ca ²⁺ mitochondrial homeostasis. The loss of mitochondrial membrane potential activates mitochondrial autophagy, which results in the release of Fe ^3+/2+ in tumor mitochondria. The released Fe ^3+/2+ can further produce more and more ROS via the Fenton reaction, which establishes the positive feedback loop of the Fenton reaction. Both in vitro and in vivo results demonstrate that MCPNC‐FH‐IO@HA exhibits remarkable antitumor efficacy, superior MRI performance, and favorable biosafety.