Semiconducting Polymer Nanoparticles with Surface‐Mimicking Protein Secondary Structure as Lysosome‐Targeting Chimaeras for Self‐Synergistic Cancer Immunotherapy

Abstract

Immunotherapy has received tremendous attention for tumor treatment, but the efficacy is greatly hindered by insufficient tumor‐infiltration of immune cells and immunosuppressive tumor microenvironment. The strategy that can efficiently activate cytotoxic T lymphocytes and inhibit negative immune regulators will greatly amplify immunotherapy outcome, which is however very rare. Herein, a new kind of semiconducting polymer (SP) nanoparticles is developed, featured with surface‐mimicking protein secondary structure (SPSS NPs) for self‐synergistic cancer immunotherapy by combining immunogenic cell death (ICD) and immune checkpoint blockade therapy. The SPs with excellent photodynamic property are synthesized by rational fluorination, which can massively induce ICD. Additionally, the peptide antagonists are introduced and self‐assembled into β‐sheet protein secondary structures on the photodynamic NP surface via preparation process optimization, which function as efficient lysosome‐targeting chimaeras (LYTACs) to mediate the degradation of programmed cell death ligand‐1 (PD‐L1) in lysosome. In vivo experiments demonstrate that SPSS NPs can not only elicit strong antitumor immunity to suppress both primary tumor and distant tumor, but also evoke long‐term immunological memory against tumor rechallenge. This work introduces a new kind of robust immunotherapy agents by combining well‐designed photosensitizer‐based ICD induction and protein secondary structures‐mediated LYTAC‐like multivalence PD‐L1 blockade, rendering great promise for synergistic immunotherapy.

Nanoparticles-based phototherapy systems for cancer treatment: Current status and clinical potential

“…It is therefore meaningful to investigate the combination of PTT/PDT and other immunotherapeutic agents, like immune checkpoint inhibitors, to achieve the best immunological activation against cancer and potentiate the abscopal effect of the treatment [ 96 ]. PTT and PDT treatments are amongst the treatments that induce immunogenic cancer cell death, leading to priming and activation of the immune system against the tumor [ 134 , [260] , [261] , [262] , [263] , [264] ].…”

Immuno-photodynamic Therapy (IPDT): Organic Photosensitizers and Their Application in Cancer Ablation

“… 136 Based on this, Ding et al constructed a new kind of semiconducting polymer (SPSS NPs) which worked along double lines, enhanced the photosensitization by organic semiconducting polymer SP3, and activated cytotoxic T lymphocytes to amplify immunotherapy by β-sheet protein degrading PD-L1 ( Figure 11 A). 137 Unlike traditional ICB therapy, this brand-new approach avoiding some potential problems such as high cost, difficulty for storage, high risk of immunogenicity, and short half-life in biological systems further guarantees its application in IPDT. The experimental results indicated that SPSS NPs can not only produce high-level ROS but also elicit strong ICD to release DAMPs, which could evoke long-term immunological memory against tumor rechallenge.…”

“… (A) Schematic illustration of SPSS NPs for self-synergistic cancer immunotherapy and its chemical structure. Reproduced from ref ( 137 ). Copyright 2022 Wiley-VCH.…”

Reactive Species-Activatable AIEgens for Biomedical Applications

“…Photodynamic therapy (PDT) is a clinically used method for treating some cancers, which is based on a light-triggered photosensitizer to generate ROS, especially the highly toxic 1 O 2 [ 135 , 136 , 137 ]. To monitor the in situ generation of 1 O 2 during PDT in real time is of comparative significance for tumor therapy and reduced side effects.…”