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Fan Quli/Xie Chen of Nanjing University of Posts and Telecommunications/Li Rutian of Nanjing University jointly reported that double-activated nano-immunomodulator can be used for precision cancer photodynamic immunotherapy.

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Photodynamic immunotherapy, which combines photodynamic therapy with immunotherapy, has become an important and effective method for the treatment of cancer. However, most cancer photodynamic immunotherapy systems cannot achieve the precise release of immunomodulators, resulting in systemic side effects and poor patient outcomes.

On October 14, 2024, Nanjing University of Posts and Telecommunications Fan Quli, Xie Chen and Nanjing University Li Rutian jointly communicatedAdvanced Science Published online entitled“Dual-Activatable Nano-Immunomodulator for NIR-II Fluorescence Imaging-Guided Precision Cancer Photodynamic Immunotherapy”of research papers.This study reports a dual-activated nano-immunomodulator (DIR NP), whose photodynamic action and agonist release can be activated under specific stimuli, and can be used for precision cancer photodynamic immunotherapy.

DIRNPs were self-assembled from an R848 conjugated amphiphilic polymer (mPEG-TK-R848) and a hydrophobic oxidized bovine serum albumin (BSA-SOH) conjugated photosensitizer (DIR).DIRNPs can produce small amounts under 808nm laser irradiation¹O₂, resulting in partial cleavage of the thioketal (TK) and release of R848 and DIR. The released DIR may bind to the tumor overexpressed BSA-SOH, increasing its photodynamic efficiency and NIR-II the fluorescence signal. This increase in photodynamic efficiency may further enhance the release of cargo after irradiation. The activated photodynamic effect induces immunogenic cell death (ICD) to release immune factors, and R848 can enhance the maturation of dendritic cells, thereby inhibiting the growth of primary and distant tumors and eliminating lung metastases.Therefore, this study provides a dual-activation smart nano-immunomodulator for precise regulation of tumor photodynamic immunotherapy.

In recent years, with the deepening understanding of immunology, photoimmunotherapy, which combines phototherapy with immunotherapy, has received widespread attention as a new and powerful tumor treatment.Typical processes of photoimmunotherapy include phototherapy induction of immunogenic cell death (ICD), dendritic cell (DC) maturation, effector T cell recruitment, and killing of primary and distant foci. Phototherapy has the advantages of high specificity and good efficacy, and can effectively induce ICD without causing serious side effects. Currently, a variety of materials have been designed for photoimmunotherapy, including semiconducting polymers, small molecule dyes, covalent organic frameworks (COFs), and inorganic nanomaterials such as metal-organic frameworks (MOFs) and gold nanomaterials. These materials can also act synergistically with Toll-like receptor (TLR) agonists to stimulate DC maturation to form multifunctional nanosystems. Such nanosystems have demonstrated excellent therapeutic effects and show great potential in cancer therapy.

Although nanosystem-mediated photoimmunotherapy holds great promise, the issue of potential side effects still needs to be addressed. In most photoimmunotherapeutic nanosystems, the two key components are photosensitizers and immune drugs (such as agonists).Photosensitizers and agonists are typically loaded into the nanoparticles through hydrophobic interactions. This structure leads to the problem of explosive release during circulation, which may lead to poor distribution of goods. Accumulation of agonists in normal tissues can lead to severe systemic immune responses and side effects. To improve specificity, various studies have designed activatable agonists for photoimmunotherapy. These agonists can only be activated or released under the stimulation of exogenous light or endogenous stimuli overexpressed by the tumor, including reactive oxygen species (ROS), GSH and enzymes, thereby achieving better tumor specificity. For the other key ingredient (photosensitizer), most photoimmunotherapeutic nanosystems employ "always-on" photosensitizers as phototherapeutic agents. Although photosensitizers exhibit photodynamic effects only when illuminated, accumulation in normal tissues surrounding tumors may lead to damage of these tissues during phototherapy.Therefore, it is necessary to improve the formulation of nanosystems to further improve the specificity of photoimmunotherapy and reduce adverse reactions.

In this study, we report a dual-activated nano-immunomodulator (DIRNP) for NIR-II fluorescence imaging-guided precision cancer photodynamic immunotherapy.DIRNPs were prepared by encapsulating DIR with mPEG2k-TK-R848 by nanoprecipitation. DIR is a 3,5-dioxane carboxylic acid (DHCA) functionalized cyanine dye (IR780), while mPEG2k-TK-R848 is an amphiphilic prodrug containing hydrophilic polyethylene glycol (PEG), ¹O ₂Responsive thioketal (TK) linker and TLR agonist (R848). As DIR aggregates within the nanoparticles, NIR-II fluorescence and PDT are greatly quenched. Under 808nm laser irradiation, DIRNPs produce a small amount ¹O ₂, ¹O ₂Cleavage of part of the TK linker releases R848 and DIR. H2O2 overexpressed in cancer cells has been reported to reversibly convert the thiol of bovine serum albumin (BSA) to sulfenic acid to form oxidized BSA(BSA-SOH), and 3,5-dioxycyclohexanecarboxylic acid (DHCA) has been reported to bind specifically to sulfenic acid. Since DIR is modified by DHCA, the released DIR can be further combined with the tumor overexpressed BSA-SOH to restore its fluorescence and greatly improve¹O₂yield (Figure 1).

¹O₂The resulting activation further leads to accelerated dissociation of DIRNPs.The entire diagnosis and treatment process of DIRNPs at the tumor site is shown in Figure 1b. DIR NPs accumulate at the tumor site and are internalized by tumor cells. Under 808nm laser irradiation, both DIR and R848 were released. The NIR-II fluorescence signal and photodynamic effect of DIR are activated by binding to BSA-SOH. Activated DIR can mediate direct tumor ablation and ICD through the photodynamic effect. In addition, the released R848 can promote dendritic cell maturation by activating TLRs on the surface of dendritic cells, thereby enhancing the immune response stimulated by ICD. Mature dendritic cells will further recruit cytotoxic T cells to kill primary and distant tumors and inhibit lung metastases. Therefore, DIRNP is a dual-activated nano-immunomodulator, and its TLR agonist and photosensitizer can be selectively activated in the tumor site for NIR-II fluorescence imaging-guided precision photoimmunotherapy.

A new photon technology makes a grand debut! Breaking traditional limitations, it will become a 'milestone' breakthrough in the development of the field!

Ultra-high-speed optical quantum detector with photon number resolution developed by Shanghai Microsystem Institute

A new photon technology makes a grand debut! Breaking traditional limitations, it will become a 'milestone' breakthrough in the development of the field!

Ultra-high-speed optical quantum detector with photon number resolution developed by Shanghai Microsystem Institute