A porphyrin-MOF-based integrated nanozyme system for catalytic cascades and light-enhanced synergistic amplification of cellular oxidative stress

Peroxidase (POD)-like nanozymes have been found to act as nanoreactors for the generation of reactive oxygen species (ROS) to resolve drug resistance in the tumor microenvironment (TME). Amplifying cellular oxidative stress is considered to be a drug-free strategy to efficiently induce apoptosis in tumor cells. However, the limited content of intracellular hydrogen peroxide (H 2 O 2 ) extremely restricts the performance of POD-like nanozymes to amplify cellular oxidative stress. Moreover, additional operational processes combined with exogenous reagents to achieve oxidative stress lead to a dilemma of extra cytotoxicity. Here, an integrated iron-porphyrin-MOF-based nanozyme composite named HA@GOx@PCN-224(Fe) (HGPF) was precisely designed and constructed. Generally, the POD-like nanozyme PCN-224(Fe) was used as a platform to immobilize glucose oxidase (GOx), and further embedded with hyaluronic acid (HA) to enable the targeting ability of tumor cells. When endocytosed by tumor cells, intracellular glucose was oxidized to H 2 O 2 and gluconic acid catalyzed by immobilized GOx of HGPF. Afterwards, inspired by heme analogs, H 2 O 2 was catalyzed by iron-porphyrin active sites of the HGPF nanozyme to generate hydroxyl radicals (&z.rad;OH). Under light irradiation, the iron-porphyrin of HGPF acted as a photosensitizer to facilely produce singlet oxygen ( 1 O 2 ). Such a synergistic generation of ROS strikingly amplified oxidative stress and induced severe apoptosis in tumor cells. HGPF was expected to integrate intracellular oxygen sources and overcome the dilemma of limited intracellular H 2 O 2 content. Consequently, HGPF was constructed as an integrated nanoreactor to simultaneously achieve light-enhanced catalytic oxidation cascades, providing a promising strategy for a synergistic amplification of cellular oxidative stress. An integrated iron-porphyrin-MOF-based nanozyme composite named HGPF was constructed for the intracellular glucose-initiated catalytic oxidation cascades and light-enhanced generation of ROS, synergistically amplifying cellular oxidative stress.