Catalytically Active Metal–Organic Frameworks Elicit Robust Immune Response to Combination Chemodynamic and Checkpoint Blockade Immunotherapy

Abstract

Chemodynamic therapy (CDT) strategies rely on the generation of reactive oxygen species (ROS) to kill tumor cells, with hydroxyl radicals (•OH) serving as the key mediators of cytotoxicity in this setting. However, the efficacy of CDT approaches is often hampered by the properties of the tumor microenvironment (TME) and associated limitations to the Fenton reaction that constrains ROS generation. As such, there is a pressing need for the design of new nanoplatforms capable of improving CDT outcomes. In this study, an Fc-based metal–organic framework (MOF) vitamin k3 (Vk3)-loaded cascade catalytic nanoplatform (Vk3@Co-Fc) was developed. This platform was capable of undergoing TME-responsive degradation without impacting normal cells. After its release, Vk3 was processed by nicotinamide adenine dinucleotide hydrogen phosphate (NAD(P)H) quinone oxidoreductase-1 (NQO1), which is highly expressed in tumor cells, thereby yielding large quantities of H2O2 that in turn interact with Fe ions via the Fenton reaction to facilitate in situ cytotoxic •OH production. This process leads to immunogenic cell death (ICD) of the tumor, which then promotes dendritic cell maturation and ultimately increases T cell infiltration into the tumor site. When this nanoplatform was combined with programmed death 1 (PD-1) checkpoint blockade approaches, it was sufficient to enhance tumor-associated immune responses in breast cancer as evidenced by increases in the frequencies of CD45+ leukocytes and CD8+ cytotoxic T lymphocytes, thereby inhibiting tumor metastasis to the lungs and improving murine survival outcomes. Together, this Vk3@Co-Fc cascading catalytic nanoplatform enables potent cancer immunotherapy for breast cancer regression and metastasis prevention.

Multifunctional nanomedicines-enabled chemodynamic-synergized multimodal tumor therapy via Fenton and Fenton-like reactions

“…For example, Au@Pt core-shell nanozyme decorated on the surface of bacteria could be promising agents of CDT in cancer treatment and the further immunotherapeutic effect was induced by bacterium-induced 164 . In another study, Fc-based MOF Vk3-loaded cascading catalytic nanoplatform was reported for enhanced CDT/immunotherapy based on Vk3-induced H 2 O 2 amplification and •OH-mediated ICD for immunotherapeutic effect 165 .…”

“…Moreover, adding physical energy fields such as light, temperature, ultrasonic field, X-ray, and magnetic field can also promote the speed of the Fenton reaction [34][35][36][37][38][39]. Another option for CDT enhancement is modulating the nutrition or immune system of the tumor to reinforce the overall therapeutic effect [40]. Numerous systems had been designed and developed based on these design principles to accelerate the Fenton reaction.…”

A review on reactive oxygen species (ROS)-inducing nanoparticles activated by uni- or multi-modal dynamic treatment for oncotherapy

“…Wang et al synthesized a vitamin k3 (Vk3) loaded cascade catalytic nanoplatform (Vk3@Co-Fc) based on a metal-organic framework (MOF) of Fc and further combined Vk3@Co-Fc-based therapy with anti-PD-1 therapy to treat the tumor. 173 The Vk3@Co-Fc was developed to improve cancer treatment with CDT. One model of 4T1 primary tumor (∼80 mm 3 ) and the other model of lung metastasis were used for in vivo experiments.…”

Current status of Fe-based MOFs in biomedical applications

“…3 The cascading catalytic VK3@Co-Fc combined with anti-PD-1 checkpoint blockade platform for enhancing antitumor immunity. 41 Copyright 2023, American Chemical Society.…”

“…3). 41 In addition to VK3, DOX (adriamycin), a first-line antitumor agent, can also increase H 2 O 2 concentration in TME. The drug DOX increases intracellular H 2 O 2 levels by activating PARP and NADPH oxidase, in addition to achieving good chemotherapeutic effects through inhibition of topoisomerase II-induced apoptosis.…”