Immunogenic cell death (ICD) provides momentous theoretical principle for modern cancer immunotherapy. However, the currently available ICD inducers are still very limited and photosensitizer‐based ones can hardly induce sufficient ICD to achieve satisfactory cancer immunotherapy by themselves. Herein, an organic photosensitizer (named TPE‐DPA‐TCyP) with a twisted molecular structure, strong aggregation‐induced emission activity, and specific ability is reported for effectively inducing focused mitochondrial oxidative stress of cancer cells, which can serve as a much superior ICD inducer to the popularly used ones, including chlorin e6 (Ce6), pheophorbide A, and oxaliplatin. Furthermore, more effective in vivo ICD immunogenicity of TPE‐DPA‐TCyP than Ce6 is also demonstrated using a prophylactic tumor vaccination model. The underlying mechanism of the effectiveness and robustness of TPE‐DPA‐TCyP in inducing antitumor immunity and immune‐memory effect in vivo is verified by immune cell analyses. This study thus reveals that inducing focused mitochondrial oxidative stress is a highly effective strategy to evoke abundant and large‐scale ICD.
Hypoxia plays crucial roles in many diseases and is a central target for them. Present hypoxia imaging is restricted to the covalent approach, which needs tedious synthesis. In this work, a new supramolecular host–guest approach, based on the complexation of a hypoxia‐responsive macrocycle with a commercial dye, is proposed. To exemplify the strategy, a carboxyl‐modified azocalix[4]arene (CAC4A) was designed that binds to rhodamine 123 (Rho123) and quenches its fluorescence. The azo groups of CAC4A were selectively reduced under hypoxia, leading to the release of Rho123 and recovery of its fluorescence. The noncovalent strategy was validated through hypoxia imaging in living cells treated with the CAC4A–Rho123 reporter pair.
Fluorescent nanoparticles (NPs) based on luminogens with aggregation-induced emission characteristic (AIEgens), namely AIE dots, have received wide attention because of their antiquenching attitude in emission and reactive oxygen species (ROS) generation when aggregated. However, few reports are available on how to control and optimize their fluorescence and ROS generation ability. Herein, it is reported that enhancing the intraparticle confined microenvironment is an effective approach to advanced AIE dots, permitting boosted cancer phototheranostics in vivo. Formulation of a "rotor-rich" and inherently charged near-infrared (NIR) AIEgen with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] and corannulene-decorated PEG affords DSPE-AIE dots and Cor-AIE dots, respectively. Compared to DSPE-AIE dots, Cor-AIE dots show 4.0-fold amplified fluorescence quantum yield and 5.4-fold enhanced ROS production, because corannulene provides intraparticle rigidity and strong interactions with the AIEgen to restrict the intramolecular rotation of AIEgen to strongly suppress the nonradiative decay and significantly facilitate the fluorescence pathway and intersystem crossing. Thus, it tremendously promotes phototheranostic efficacies in terms of NIR image-guided cancer surgery and photodynamic therapy using a peritoneal carcinomatosis-bearing mouse model. Collectively, it not only provides a novel strategy to advanced AIE dots for cancer phototheranostics, but also brings new insights into the design of superior fluorescent NPs for biomedical applications.
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.
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