Covalent organic frameworks-derived carbon nanospheres based nanoplatform for tumor specific synergistic therapy via oxidative stress amplification and calcium overload

Combinational therapy in cancer treatment that integrates the merits of different therapies is an effective approach to improve therapeutic outcomes. Herein, a simple nanoplatform (N-CNS-CaO₂-HA/Ce6 NCs) that synergized chemodynamic therapy (CDT), photodynamic therapy (PDT), photothermal therapy (PTT), and Ca²⁺ interference therapy (CIT) has been developed to combat hypoxic tumors. With high photothermal effect, excellent peroxidase-like activity, and inherent mesoporous structure, N-doped carbon nanospheres (N-CNSs) were prepared via in situ pyrolysis of an established nanoscale covalent organic frameworks (COFs) precursor. These N-CNSs acted as PTT/CDT agents and carriers for the photosensitizer chlorin e6 (Ce6), thereby yielding a minimally invasive PDT/PTT/CDT synergistic therapy. Hyaluronic acid (HA)-modified CaO₂ nanoparticles (CaO₂-HA NPs) coated on the surface of the nanoplatform endowed the nanoplatform with O₂/H₂O₂ self-supply capability to respond to and modulate the tumor microenvironment (TME), which greatly facilitated the tumor-specific performance of CDT and PDT. Moreover, the reactive oxygen species (ROS) produced during PDT and CDT enhanced the Ca²⁺ overloading due to CaO₂ decomposition, amplifying the intracellular oxidative stress and leading to mitochondrial dysfunction. Notably, the HA molecules not only increased the cancer-targeting efficiency but also prevented CaO₂ degradation during blood circulation, providing double insurance of tumor-selective CIT. Such a nanotherapeutic system possessed boosted antitumor efficacy with minimized systemic toxicity and showed great potential for treating hypoxic tumors.