Protein-Delivering Nanocomplexes with Fenton Reaction-Triggered Cargo Release to Boost Cancer Immunotherapy

Abstract

Immunotherapeutic efficacy of tumors based on immune checkpoint blockade (ICB) therapy is frequently limited by an immunosuppressive tumor microenvironment and cross-reactivity with normal tissues. Herein, we develop reactive oxygen species (ROS)-responsive nanocomplexes with the function of ROS production for delivery and triggered release of anti-mouse programmed death ligand 1 antibody (αPDL1) and glucose oxidase (GOx). GOx and αPDL1 were complexed with oligomerized (−)-epigallocatechin-3-O-gallate (OEGCG), which was followed by chelation with Fe 3+ and coverage of the ROS-responsive block copolymer, POEGMA-b-PTKDOPA, consisting of poly(oligo(ethylene glycol)methacrylate) (POEGMA) and the block with thioketal bond-linked dopamine moieties (PTKDOPA) as the side chains. After intravenous injection, the nanocomplexes show prolonged circulation in the bloodstream with a half-life of 8.72 h and efficient tumor accumulation. At the tumor sites, GOx inside the nanocomplexes can produce H 2 O 2 via oxidation of glucose for Fenton reaction to generate hydroxyl radicals (•OH) which further trigger the release of the protein cargos through ROSresponsive cleavage of thioketal bonds. The released GOx improves the production efficiency of •OH to kill cancer cells for release of tumor-associated antigens via chemodynamic therapy (CDT). The enhanced immunogenic cell death (ICD) can activate the immunosuppressive tumor microenvironment and improve the immunotherapy effect of the released αPDL1, which significantly suppresses primary and metastatic tumors. Thus, the nanocomplexes with Fenton reaction-triggered protein release show great potentials to improve the immunotherapeutic efficacy of ICB via combination with CDT.

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

“…Copyright 2020, American Chemical Society. (B) Schematic illustration for the a) preparation of P/G@EF-TKNPs and b) mechanism of in vivo CombinationTherapy of CDT and ICB 161 . Copyright 2022, American Chemical Society.…”

“…Moreover, the released αPDL1 bound specifically to PDL1 on tumor cells for ICB. Finally, the nanocomplexes induced superior systemic immune responses, effectively inhibiting the growth of primary and distant tumors in the mice bilateral 4T1 tumor models 161 .…”

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“…423,424 CDT, a noninvasive treatment with a high tissue penetration depth compared to phototherapy strategies, can generate ROS via Fenton or Fenton-like reactions or sonosensitizers to induce tumor ablation, enhance immunogenicity, and achieve better antitumor immunity. [424][425][426] For instance, alendronate (ALD)/K7M2 cell membrane-encapsulated hollow manganese dioxide (HMnO 2 ) nanoplatforms were used as nanocarriers to encapsulate ginsenoside Rh2 (Rh2) for magnetic resonance imaging (MRI)-guided chemodynamic-immunotherapy combination treatment in osteosarcoma. 427 ALD and K7M2 cell membranes were successively modified on the surface of the nanoparticles and encapsulated with Rh2.…”

Nanomaterials: small particles show huge possibilities for cancer immunotherapy

“…However, tumor hypoxia and difficulty in Fenton reaction induction limit its application. The practical component for inducing ROS production in the Fenton reaction is Fe 2+ rather than Fe 3+ , and if recycling of Fe 2+ is achieved, it is crucial for efficient induction of ROS production [ 86 – 88 ]. Yao et al [ 89 ] proposed to use a core of iron porphyrin-based MOF, doped with Pt nanoparticles and then modified with erythrocyte membranes in the outermost layer to obtain FTP@RBCM as an enforcer of the radical storm.…”