Staggered Stacking Covalent Organic Frameworks for Boosting Cancer Immunotherapy

Abstract

The synergistic efficacy of phototherapy and cancer immunotherapy is severely restricted by both the inherent photobleaching and aggregation‐caused quench (ACQ) defects of photosensitizers and the intrinsic antioxidant tumor microenvironment (TME), such as hypoxia and overexpressed glutathione (GSH). To address these issues, a novel porphyrin‐based staggered stacking covalent organic framework (COF), COF‐618‐Cu, is rationally designed as a reactive oxygen species (ROS) amplifier, owing to its excellent catalase‐like activity, COF‐618‐Cu is capable of consuming endogenous hydrogen peroxide to produce sufficient oxygen to alleviate the tumor hypoxia phenomena. Moreover the overexpressed intracellular GSH is also depleted to decrease the scavenging of ROS, due to the glutathione peroxidase mimic activity of COF‐618‐Cu. Mechanistic studies reveal that the unique staggered stacking mode between COF‐618‐Cu interlayers can effectively relieve both the photobleaching and ACQ effects that are inaccessible to commonly eclipsed COFs. These, combined with their excellent photothermal therapy performance, make COF‐618‐Cu favorable for inducing robust immunogenic cell death and remodeling TME to boost antitumor immunity.

A vinyl-decorated covalent organic framework for ferroptotic cancer therapy via visible-light-triggered cysteine depletion

“…The application of nanoscale COFs in antitumor therapy, such as drug delivery, [79][80][81] phototherapy, [82][83][84][85][86] and immunotherapy, [87][88][89] has attracted extensive research interest, and the practicability and effectiveness of COFs as nanocarriers have been well demonstrated. However, antitumor therapy based on intracellular light-triggered modification of COFs has not been realized.…”

Applications of Covalent Organic Frameworks (COFs) in Oncotherapy

“…[45]. Copyright 2021, Wiley-VCH; and (c) COF-618-Cu for enhancing antitumor immunity: Different structures between overlapped-stacked COFs and staggered-stacking COFs; Biological processes and underlying mechanisms of COF-618-Cu-mediated PDT and PTT for triggering cancer immunotherapy [46]. Reproduced with permission from ref.…”

“…Mechanistic studies show that the unique staggered-stacked pattern between the COF-618-Cu interlayers can alleviate the photobleaching and ACQ effects that cannot be obtained with ordinary COFs. Furthermore, COF-618-Cu, coupled with its excellent photothermal properties, is beneficial to inducing robust immunogenic cell death and remodeling TME to enhance antitumor immune effects [46].…”

A rigidity–flexibility balance strategy enabling highly photoluminescent two-dimensional covalent organic framework nanosheets

“…A strong p-interaction between adjacent layers in 2D COFs with rigid building blocks could easily trigger the thermal decay of excitons, leading to weak or non-photoluminescence (PL), known as the aggregation-caused quenching (ACQ) effect. 14,17,18 To reduce the interlayer p-p interaction, flexible building blocks were introduced into COFs. 19 However, the unrestricted intramolecular rotation and vibration can stabilize the molecular excited state by structural relaxation, which can also induce non-radiative energy decay, leading to weakened or no fluorescence emission.…”