Chen Xie

Photoimmunotherapy (PIT) has emerged as a promising modality for colorectal cancer (CRC) treatment, yet it often suffers from limited response rates and immune escape. We herein report a carrier‐free, tumor‐specific nanomodulator (IRP@Cu‐R) for near‐infrared second window (NIR‐II) fluorescence imaging‐guided cuproptosis‐augmented PIT of CRC. IRP@Cu‐R is prepared by co‐assembly of IRP@Cu, which is synthesized by linking a NIR‐II fluorophore (IR820) with a photosensitizer (PPa) through Cu ²⁺ ‐chelated DTPA, and a boronic ester‐masked immune adjuvant (R848‐PB) without additional nanocarrier. The drug loading contents for PPa and R848‐PB are as high as 21.1% and 17.8%, respectively. With Cu ²⁺ coordinated, both NIR‐II fluorescence and photodynamic activity are quenched via photoinduced electron transfer (PeT). Upon exposure to endogenous hydrogen sulfide (H ₂ S), Cu ²⁺ is converted to CuS, thereby restoring both activities. The released Cu ²⁺ is reduced to Cu ⁺ by glutathione (GSH), depleting antioxidants and inducing cuproptosis via lipoylated protein aggregation. Together with PDT, this process enhances immunogenic cell death. Meanwhile, excess H ₂ O ₂ cleaves the boronic ester bond of R848‐PB to release R848. These processes promote dendritic cell maturation, thereby eliciting potent systemic antitumor immunity against primary, distant and metastatic tumors. Thus, this study provides a generalizable carrier‐free strategy for integrating activatable NIR‐II fluorescence imaging with cuproptosis‐augmented photoimmunotherapy.

The rupture of atherosclerotic plaques is a crucial event leading to acute cardiovascular incidents like myocardial infarction and stroke, and accurate imaging of atherosclerotic plaques is of great significance. Currently, early and precise diagnosis of atherosclerosis (AS) is still a challenge because of the lack of suitable diagnostic methods and probes. Herein, we develop a novel cascade‐activatable nanoprobe IR820‐PDA@BSA‐T, which can sequentially respond to AS‐overexpressed protein disulfide isomerase (PDI) and high viscosity microenvironment, for second near‐infrared window (NIR‐II) fluorescence/photoacoustic imaging of AS. IR820‐PDA@BSA‐T was prepared by encapsulating a small‐molecular dye IR820‐PDA with bovine serum albumin (BSA), and then conjugating AS‐targetable peptide VVGS onto its surface. Upon the activation of PDI, the NIR‐II fluorescence intensity and ratiometric photoacoustic signal (PA ₈₄₀ /PA ₆₇₀ ) of IR820‐PDA are significantly enhanced. The high viscosity restricts the intramolecular rotation of activated IR820‐PDA, leading to the further elevation of NIR‐II fluorescence signal. In atherosclerotic mouse model, IR820‐PDA@BSA‐T accurately targets plaque regions, achieving a total 8.3‐ and 13.9‐fold increases of PA ₈₄₀ /PA ₆₇₀ and NIR‐II fluorescence signal, respectively, compared with normal vessels. Therefore, this research establishes IR820‐PDA@BSA‐T as a smart and multi‐modality nanoprobe for AS imaging with high sensitivity and resolution, providing novel thoughts for precise imaging of cardiovascular diseases.

We construct an activatable nanoplatform with dual quenching. Tumor-overexpressed glutathione triggers the system to achieve synergistic photodynamic, chemodynamic and photothermal therapy for enhanced antitumor efficacy. Created with Biorender.com.

Photoimmunotherapy is a promising therapeutic modality which utilizes phototherapy to trigger immune responses for cancer therapy. However, the requirement of light to trigger the therapeutic procedure greatly suppress its efficacy...

Colorectal cancer (CRC) is among the malignancies with the highest morbidity, and accurate diagnosis and therapy are essential for improving patient survival. However, CRC is usually diagnosed at an advanced stage, and complete resection of the tumor lesion during treatment is difficult. Herein, we develop a cascade-activatable NIR-II fluorescent inhibitor (Cu@IR783-CAI) for imaging-guided cuproptosis/chemodynamic combination therapy of CRC. Cu@IR783-CAI is synthesized by sequentially modifying a copper complex and a benzenesulfonamide moiety onto NIR-II fluorescent dye IR783. The NIR-II fluorescence signal is quenched by the copper complex via a donor-excited photoinduced electron transfer (d-PeT) process under physiological conditions. In the CRC microenvironment, the overexpressed hydrogen sulfide (H₂S) can react with the copper complex to generate copper sulfide, which hinders the d-PeT process and recovers the NIR-II fluorescence signal. Furthermore, Cu@IR783-CAI targets carbonic anhydrase IX (CA IX), which is overexpressed on the surface of tumor cells, thereby restricting intramolecular rotation and further enhancing the NIR-II fluorescence signal, thus achieving cascade activation. In addition, the copper complex of Cu@IR783-CAI can simultaneously trigger cuproptosis and chemodynamic therapy within tumor cells, demonstrating satisfactory anticancer efficacy both in vitro and in vivo. Thus, our study provides a smart NIR-II fluorescent CA inhibitor with cascade-activatable features for CRC theranostics.

In situ and metastatic malignant tumors are primary diseases that threaten human life. Among all the metastases, liver metastasis is the most difficult to detect. As most imaging probes have high liver accumulation, it is difficult to distinguish tiny metastases from normal liver tissue with strong background signal. In this study, the design of a novel second near‐infrared window (NIR‐II) fluorescence probe for precise detection of carcinoma in situ and liver metastases is presented. The probe called Tg‐RGD utilizes a commercially available cyanine dye IR‐806 as the signaling moiety, a disulfide bond linker as the responsive moiety, an RGD‐capped poly(ethylene glycol) (PEG) as the water soluble enhancer, and the tumor targeting moiety. Tg‐RGD shows good glutathione (GSH) responsiveness and selectivity, where its NIR‐II fluorescence intensity can enhance 50‐fold after activation. In vivo study indicates that Tg‐RGD shows much better imaging and targeting effects than Tg‐PEG with a similar structure but without RGD moiety for both orthotopic breast cancer and osteosarcoma. Most importantly, Tg‐RGD can detect tiny liver metastases with high signal‐to‐background ratio (3.2). Thus, this study reports a high‐performance tumor‐specific NIR‐II fluorescence probe for in situ and tiny metastatic tumor detection, and may further broaden the applications into related tumor lesions.

This work developed endoplasmic reticulum (ER)-targeting activatable nanophotosensitizers, which can selectively release ER-targeting photosensitizers and YC-1 within tumor cells for enhanced photodynamic therapy and hypoxia relief, respectively.

Semiconducting polymer nanoparticles (SPNs) have been widely applied for phototheranostics. However, the disadvantage of in vivo long-term metabolism greatly suppresses the clinical application of SPNs. To improve the metabolic rate and minimize the long-term toxicity of SPNs, biodegradable semiconducting polymers (BSPs), whose backbones may be degraded under certain conditions, have been designed. This review summarizes recent advances in BSP-constructed nanoparticles (BSPNs) for phototheranostics. BSPs are divided into two categories: conjugated backbone degradable BSPs (CBD-BSPs) and non-conjugated backbone degradable BSPs (NCBD-BSPs), based on the feature of chemical structure. The biological applications, including cancer imaging and combination therapy, of these BSPNs are described. Finally, the conclusion and future perspectives of this field are discussed.

Photodynamic immunotherapy which combines photodynamic therapy with immunotherapy has become an important and effective method for the treatment of cancer. However, most cancer photodynamic immunotherapeutic systems are not able to achieve precise release of immunomodulators, resulting in systemic side effects and poor patient outcomes. Herein, a dual‐activatable nano‐immunomodulator (DIR NP), which both its photodynamic effect and agonist release can be activated under specific stimuli, is reported for precision cancer photodynamic immunotherapy. The DIR NP is self‐assembled from an R848‐conjugated amphiphilic polymer (mPEG‐TK‐R848) and a hydrophobic oxidized bovine serum albumin (BSA‐SOH)‐conjugatable photosensitizer (DIR). DIR NPs may generate a small amount of ¹O₂ under 808 nm laser irradiation, leading to the cleavage of thioketal (TK) moiety and release of R848 and DIR. The released DIR may conjugate with tumor‐overexpressed BSA‐SOH, improving its photodynamic efficiency and NIR‐II fluorescence signal. Such photodynamic efficiency improvement may further enhance the release of cargoes upon irradiation. The activated photodynamic effect induces immunogenic cell death (ICD) to release immune factors and R848 can enhance the maturation of dendritic cells for inhibiting the growth of both primary and distant tumors and eliminating lung metastasis. Therefore, this study provides a dual‐activatable intelligent nano‐immunomodulator for precise regulation of tumor photodynamic immunotherapy.