Calcium peroxide functionalized mesoporous polydopamine nanoparticles triggered calcium overload for synergistic...

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 (Ca²⁺) overload therapy has emerged as a promising strategy for inducing tumor cell apoptosis. However, existing methods that rely on direct Ca²⁺ delivery often face limited efficacy due to tumor adaptation mechanisms. In this study, we developed a multifunctional nanoparticle system (MLCH NPs) that synergistically combines Ca²⁺ 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 (CaO₂), with hyaluronic acid (HA) modification to ensure tumor targeting and protect CaO₂ from premature degradation. In the tumor microenvironment (TME), MLCH NPs released Ca²⁺, hydrogen peroxide (H₂O₂), and nitric oxide (NO), creating a self-sustaining Ca²⁺-H₂O₂-NO cycle that induced oxidative stress, mitochondrial damage, and sustained Ca²⁺ overload, leading to tumor cell apoptosis. The nanoparticles also harnessed the photothermal effect under 808 nm near-infrared irradiation to amplify NO and Ca²⁺ 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 Ca²⁺ overload, GT, and PTT. This study proposes a novel platform for Ca²⁺/NO co-delivery and offers a promising approach for enhancing tumor therapies based on Ca²⁺ overload.