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Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy (PDT) due to oxygen consumption. Type I PDT, which can operate independently of oxygen, is a viable option for treating hypoxic tumors. In this study, we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment (TME) to enhance type I PDT through glutathione (GSH) depletion. Our approach aims to expand the sources of therapeutic benefits by promoting the generation of superoxide radicals (O2−.) while minimizing their consumption. The diisopropyl group within PEG-IR820 serves a dual purpose: it functions as a pH sensor for the disassembly of the NPs to release JSK and enhances intermolecular electron transfer to IR820, facilitating efficient O2−. generation. Simultaneously, the release of JSK leads to GSH depletion, resulting in the generation of nitric oxide (NO). This, in turn, contributes to the formation of highly cytotoxic peroxynitrite (ONOO−.), thereby enhancing the therapeutic efficacy of these NPs. NIR-II fluorescence imaging guided therapy has achieved successful tumor eradication with the assistance of laser therapy. We proposed the new concept of “broadening sources” by enhancing O2−. generation and “reducing expenditure” by diminishing O2−. consumption. The diisopropyl groups in JSK@PEG-IR820 function as a pH sensor for the disassembly of the NPs to release JSK and enhances intermolecular electron transfer to IR820, facilitating efficient O2−. generation. Simultaneously, the release of JSK leads to GSH depletion, resulting in the generation of nitric oxide (NO). The reaction between O2−. and NO will generate higher cytotoxic ONOO−., leading to the complete regression of tumor. Illustration of synthesis of JSK@PEG-IR820 for NO therapy enhanced type I PDT. [Display omitted] •JSK@PEG-IR820 nanoparticles (NPs) have been designed and synthesized.•The NPs can be triggered by acidity to release JSK for GSH depletion activated NO generation.•The intermolecular electron transfer facilitates the O2−. generation.•The reaction between O2−. and NO generates higher cytotoxic ONOO−., leading to the complete tumor regression.

Bacterial infection in skin and soft tissue has emerged as a critical concern. Overreliance on antibiotic therapy has led to numerous challenges, including the emergence of multidrug-resistant bacteria and adverse drug reactions. It is imperative to develop non-antibiotic treatment strategies that not only exhibit potent antibacterial properties but also promote rapid wound healing and demonstrate biocompatibility. Herein, a novel multimodal synergistic antibacterial system (SNO-CS@MoS 2 ) was developed. This system employs easily surface-modified thin-layer MoS 2 as photothermal agents and loaded with S-nitrosothiol-modified chitosan (SNO-CS) via electrostatic interactions, thus realizing the combination of NO gas therapy and photothermal therapy (PTT). Furthermore, this surface modification renders SNO-CS@MoS 2 highly stable and capable of binding with bacteria. Through PTT’s thermal energy, SNO-CS@MoS 2 rapidly generates massive NO, collaborating with PTT to achieve antibacterial effects. This synergistic therapy can swiftly disrupt the bacterial membrane, causing protein leakage and ATP synthesis function damage, ultimately eliminating bacteria. Notably, after effectively eliminating all bacteria, the residual SNO-CS@MoS 2 can create trace NO to promote fibroblast migration, proliferation, and vascular regeneration, thereby accelerating wound healing. This study concluded that SNO-CS@MoS 2 , a novel multifunctional nanomaterial with outstanding antibacterial characteristics and potential to promote wound healing, has promising applications in infected soft tissue wound treatment.

Theranostic nanodrugs combining magnetic resonance imaging (MRI) and cancer therapy have attracted extensive interest in cancer diagnosis and treatment. Herein, a manganese (Mn)-doped mesoporous polydopamine (Mn-MPDA) nanodrug incorporating the nitric oxide (NO) prodrug BNN6 and immune agonist R848 was developed. The nanodrug responded to the H + and glutathione being enriched in tumor microenvironment to release R848 and Mn 2+ . The abundant Mn 2+ produced through a Fenton-like reaction enabled a highly sensitive T1–T2 dual-mode MRI for monitoring the tumor accumulation process of the nanodrug, based on which an MRI-guided laser irradiation was achieved to trigger the NO gas therapy. Meanwhile, R848 induced the re-polarization of tumor-promoting M2-like macrophage to a tumoricidal M1 phenotype. Consequently, a potent synergistic antitumor effect was realized in mice bearing subcutaneous 4T1 breast cancer, which manifested the great promise of this multifunctional nanoplatform in cancer treatment.

The tumor microenvironment (TME) significantly restricts chemodynamic therapy (CDT) efficacy through hypoxia and antioxidant defenses. An intelligent cascade nanosystem, PTA‐SnS2@GOx, is developed by integrating a tannic acid‐modified Prussian blue analogue core, SnS2 shell, and glucose oxidase (GOx) activation module. The needle‐like nanostructure enhanced tumor accumulation and cellular uptake. GOx‐mediated glucose oxidation generated H2O2 and gluconic acid, triggering pH‐responsive H2S release from SnS2. This gas disrupted mitochondrial respiration and catalase activity, alleviating hypoxia while elevating intracellular H2O2 levels. The oxygenated TME subsequently amplified GOx biocatalysis, establishing a self‐sustaining cycle of H2O2 production and acidification. Concurrently, Sn4+ ions depleted glutathione, synergistically enhancing Fenton‐like reactions in the PTA core for reinforced ROS generation. This multi‐tiered strategy achieved effective CDT through the coordinated mechanisms: continuous H2O2 self‐supply, pH reduction, and redox homeostasis disruption. Notably, the nanosystem induced immunogenic cell death, promoting dendritic cell maturation and repolarizing tumor‐associated macrophages from M2 to M1 phenotype, thereby remodeling immunosuppressive TME and activating systemic antitumor immunity. The synergistic integration of self‐amplifying CDT with immune sensitization demonstrates superior tumor suppression in vivo. This study provided an intelligent paradigm for cancer theranostics by combining self‐supplying H2S/H2O2‐enhanced CDT with sensitized immunotherapy. The PTA‐SnS2@GOx cascade nanosystem presents a smart paradigm for cancer theranostics, integrating self‐supplied H2S/H2O2‐augmented chemodynamic therapy (CDT) with sensitized immunotherapy. Its needle‐like SnS2 shell enhances tumor‐specific uptake, ensuring biosafety. This responsive strategy pioneers heteromorphic metal sulfide nanostructures in modulating surface topology for optimized therapeutic efficacy, demonstrating translational potential in precision oncology.

ABSTRACT Near‐infrared II (NIR‐II) fluorescent nanoparticles (NPs) based on aggregation‐induced emission (AIE) have attracted significant attention due to their multimodal imaging capabilities as well as the combined photothermal and photodynamic therapeutic effects in cancer therapy. Reported herein is the rational designed AIE molecule (BPT), via incorporating phenothiazine units with strong electron‐donating and reactive oxygen species (ROS) generation capabilities into the classical AIE scaffold tetraphenylethylene, further coupled with a strong electron‐acceptor named benzo[1,2‐c:4,5‐c']bis[1,2,5]thiadiazole. The BPT NPs exhibited maximum NIR‐II fluorescence emission at 1083 nm, a fluorescence quantum yield of 1.53%, photothermal conversion efficiency of 63%, and photoacoustic imaging capabilities, alongside considerable type I ROS generation ability. Additionally, when a kind of nitric oxide (NO) donor named O2‐(2,4‐dinitrophenyl) 1‐[(4‐ethoxycarbonyl) piperazin‐1‐yl]diazen‐1‐ium‐1,2‐diolate (JSK) was incorporated, the corresponding JSK‐BPT NPs could generate O2−, NO, and peroxynitrite to induce phototoxicity. By applying it to the 4T1 breast tumor model, JSK‐BPT NPs achieved high‐quality multimodal imaging of the vasculature and tumor regions in mice. Under the multimodal imaging guidance, the 4T1 tumor could be ablated completely after a single dose of JSK‐BPT NPs and under the irradiation of an 808 nm laser. Reported herein is the rational‐designed aggregation‐induced emission molecule (BPT), its nanoparticles (BPT NPs), and further processed heat and peroxynitrite generating nanoplatform for precision multimodal imaging‐guided tumor phototherapy. This nanoplatform showed near‐infrared II fluorescence, photothermal, and photoacoustic imaging capabilities, together with efficient heat production and multiple reactive oxygen species generation capacities, achieving complete tumor ablation with a single dose under the guidance of tri‐modal imaging in the 4T1 mouse tumor model.

Photothermal therapy (PTT) has garnered significant attention in recent years, but the standalone application of PTT still faces limitations that hinder its ability to achieve optimal therapeutic outcomes. Nitric oxide (NO), being one of the most extensively studied gaseous molecules, presents itself as a promising complementary candidate for PTT. In response, various nanosystems have been developed to enable the simultaneous utilization of PTT and NO‐mediated gas therapy (GT), with the integration of photothermal agents (PTAs) and thermally‐sensitive NO donors being the prevailing approach. This combination seeks to leverage the synergistic effects of PTT and GT while mitigating the potential risks associated with gas toxicity through the use of a single laser irradiation. Furthermore, additional internal or external stimuli have been employed to trigger NO release when combined with different types of PTAs, thereby further enhancing therapeutic efficacy. This comprehensive review aims to summarize recent advancements in NO gas‐assisted cancer photothermal treatment. It commences by providing an overview of various types of NO donors and precursors, including those sensitive to photothermal, light, ultrasound, reactive oxygen species, and glutathione. These NO donors and precursors are discussed in the context of dual‐modal PTT/GT. Subsequently, the incorporation of other treatment modalities such as chemotherapy (CHT), photodynamic therapy (PDT), alkyl radical therapy, radiation therapy, and immunotherapy (IT) in the creation of triple‐modal therapeutic nanoplatforms is presented. The review further explores tetra‐modal therapies, such as PTT/GT/CHT/PDT, PTT/GT/CHT/chemodynamic therapy (CDT), PTT/GT/PDT/IT, PTT/GT/starvation therapy (ST)/IT, PTT/GT/Ca2+ overload/IT, PTT/GT/ferroptosis (FT)/IT, and PTT/GT/CDT/IT. Finally, potential challenges and future perspectives concerning these novel paradigms are discussed. This comprehensive review is anticipated to serve as a valuable resource for future studies focused on the development of innovative photothermal/NO‐based cancer nanotheranostics. A comprehensive review summarizes recent advancements in nitric oxide (NO) gas‐assisted cancer photothermal treatment. It commences by providing various types of NO donors/precursors for dual‐modal therapy. Subsequently, chemotherapy, photodynamic therapy, alkyl radical therapy, radiation therapy, immunotherapy, chemodynamic therapy, starvation therapy, Ca2+ overload, and ferroptosis are incorporated for triple‐ and tetra‐modal treatment.

Tumor microenvironment (TME)‐triggered phototheranostic platform offers a feasible strategy to improve cancer diagnosis accuracy and minimize treatment side effects. Developing a stable and biocompatible molecular phototheranostic platform for TME‐activated second near‐infrared (NIR‐II) fluorescence imaging‐guided multimodal cascade therapy is a promising strategy for creating desirable anticancer agents. Herein, a new NIR‐II fluorescence imaging‐guided activatable molecular phototheranostic platform (IR‐FEP‐RGD‐S‐S‐S‐Fc) is presented for actively targeted tumor imaging and hydrogen sulfide (H2S) gas‐enhanced chemodynamic‐hypothermal photothermal combined therapy (CDT/HPTT). It is revealed for the first time that the coupling distance between IR‐FE and ferrocene is proportional to the photoinduced electron transfer (PET), and the aqueous environment is favorable for PET generation. The part of Cyclic‐RGDfK (cRGDfk) peptides can target the tumor and benefit the endocytosis of nanoparticles. The high‐concentration glutathione (GSH) in the TME will separate the fluorescence molecule and ferrocene by the GSH‐sensitive trisulfide bond, realizing light‐up NIR‐II fluorescence imaging and a cascade of trimodal synergistic CDT/HPTT/gas therapy (GT). In addition, the accumulation of hydroxyl radicals (•OH) and down‐regulation of glutathione peroxidase 4 (GPX4) can produce excessive harmful lipid hydroperoxides, ultimately leading to ferroptosis. Trisulfide bond‐mediated molecular phototheranostic platform for “activatable” NIR‐II imaging‐guided enhanced gas‐chemo‐hypothermal photothermal therapy. A new phototheranostic platform is developed, utilizing cyclic‐RGDfk (cRGDfk) peptide for active tumor cell targeting and achieving glutathione (GSH)‐rich tumor environment photoinduced electron transfer (PET) blockade for fluorescence‐specific illumination and therapy.

Gas‐mediated sonodynamic therapy (SDT) has the potential to become an effective strategy to improve the therapeutic outcome and survival rate of cancer patients. Herein, titanium sulfide nanosheets (TiSX NSs) are prepared as cascade bioreactors for sequential gas–sonodynamic cancer therapy. TiSX NSs themselves as hydrogen sulfide (H2S) donors can burst release H2S gas. Following H2S generation, TiSX NSs are gradually degraded to become S‐defective and partly oxidized into TiOX on their surface, which endows TiSX NSs with high sonodynamic properties under ultrasound (US) irradiation. In vitro and in vivo experiments show the excellent therapeutic effects of TiSX NSs. In detail, large amounts of H2S gas and reactive oxygen species (ROS) can simultaneously inhibit mitochondrial respiration and ATP synthesis, leading to cancer cell apoptosis. Of note, H2S gas also plays important roles in modulating and activating the immune system to effectively inhibit pulmonary metastasis. Finally, the metabolizable TiSX NSs are excreted out of the body without inducing any significant long‐term toxicity. Collectively, this work establishes a cascade bioreactor of TiSX NSs with satisfactory H2S release ability and excellent ROS generation properties under US irradiation for programmed gas–sonodynamic cancer therapy. Titanium sulfide (TiSX) nanosheets synthesized via a convenient high‐temperature organic‐phase method are used as a cascade bioreactor for H2S‐mediated programmed gas–sonodynamic cancer therapy.

Gas therapy, a burgeoning clinical treatment modality, has garnered widespread attention to treat a variety of pathologies in recent years. The advent of nanoscale gas drug therapy represents a novel therapeutic strategy, particularly demonstrating immense potential in the realm of oncology. This comprehensive review navigates the landscape of gases endowed with anti-cancer properties, including hydrogen (H ), carbon monoxide (CO), carbon dioxide (CO ), nitric oxide (NO), oxygen (O ), sulfur dioxide (SO ), hydrogen sulfide (H S), ozone (O ), and heavier gases. The selection of optimal delivery vectors is also scrutinized in this review to ensure the efficacy of gaseous agents. The paper highlights the importance of engineering stimulus-responsive delivery systems that enable precise and targeted gas release, thereby augmenting the therapeutic efficiency of gas therapy. Additionally, the review examines the synergistic potential of integrating gas therapy with conventional treatments such as starvation therapy, ultrasound (US) therapy, chemotherapy, radiotherapy (RT), and photodynamic therapy (PDT). It also discusses the burgeoning role of advanced multimodal and US imaging in enhancing the precision of gas therapy applications. The insights presented are pivotal in the strategic development of nanomedicine platforms designed for the site-specific delivery of therapeutic gases, heralding a new era in cancer therapeutics.