Calcium peroxide functionalized mesoporous polydopamine nanoparticles triggered calcium overload for synergistic tumor gas/photothermal therapy.

Cancer remains a significant global health challenge due to its high mortality rates and the limitations of conventional therapies, which are often associated with severe side effects and limited efficacy. Calcium (Ca) overload therapy has emerged as a promising strategy for inducing tumor cell apoptosis. However, existing methods that rely on direct Ca delivery often face limited efficacy due to tumor adaptation mechanisms. In this study, we developed a multifunctional nanoparticle system (MLCH NPs) that synergistically combines Ca overload, gas therapy (GT), and photothermal therapy (PTT). This nanoparticle system was based on mesoporous polydopamine (MPDA) nanoparticles loaded with l-arginine (LA) and calcium peroxide (CaO), with hyaluronic acid (HA) modification to ensure tumor targeting and protect CaO from premature degradation. In the tumor microenvironment (TME), MLCH NPs released Ca, hydrogen peroxide (HO), and nitric oxide (NO), creating a self-sustaining Ca-HO-NO cycle that induced oxidative stress, mitochondrial damage, and sustained Ca overload, leading to tumor cell apoptosis. The nanoparticles also harnessed the photothermal effect under 808 nm near-infrared irradiation to amplify NO and Ca release, enhancing oxidative stress and sensitizing tumor cells. Both in vitro and in vivo studies confirmed that MLCH NPs significantly suppressed tumor progression through the synergistic effects of Ca overload, GT, and PTT. This study proposes a novel platform for Ca/NO co-delivery and offers a promising approach for enhancing tumor therapies based on Ca overload.