Multifunctional Calcium-Manganese Nanomodulator Provides Antitumor Treatment and Improved Immunotherapy via Reprogramming of the Tumor Microenvironment.

Ions play a vital role in regulating various biological processes, including metabolic and immune homeostasis, which involves tumorigenesis and therapy. Thus, the perturbation of ion homeostasis can induce tumor cell death and evoke immune responses, providing specific antitumor effects. However, antitumor strategies that exploit the effects of multiion perturbation are rare. We herein prepared a pH-responsive nanomodulator by coloading curcumin (CU, a Ca2+ enhancer) with CaCO3 and MnO2 into nanoparticles coated with a cancer cell membrane. This nanoplatform was aimed at reprogramming the tumor microenvironment (TME) and providing an antitumor treatment through ion fluctuation. The obtained nanoplatform, called CM NPs, could neutralize protons by decomposing CaCO3 and attenuating cellular acidity, they could generate Ca2+ and release CU, elevating Ca2+ levels and promoting ROS generation in the mitochondria and endoplasmic reticulum, thus, inducing immunogenic cell death. Mn2+ could decompose the endogenous H2O2 into O2 to relieve hypoxia and enhance the sensitivity of cGAS, activating the cGAS-STING signaling pathway. In addition, this strategy allowed the reprogramming of the immune TME, inducing macrophage polarization and dendritic cell maturation via antigen cross-presentation, thereby increasing the immune system's ability to combat the tumor effectively. Moreover, the as-prepared nanoparticles enhanced the antitumor responses of the αPD1 treatment. This study proposes an effective strategy to combat tumors via the reprogramming of the tumor TME and the alteration of essential ions concentrations. Thus, it shows great potential for future clinical applications as a complementary approach along with other multimodal treatment strategies.

Bacteria-targeted delivery of black phosphorus quantum dots facilitates photothermal therapy against hypoxic tumors and complementary low-dose radiotherapy.

Many approaches have been employed to relieve hypoxia in solid tumors to enhance sensitivity to radiotherapy (RT), including O2 delivery or hydrogen peroxide (H2O2) decomposition strategies. To date, however, these modalities have been restricted by poor O2 loading, rapid O2 leakage, and limited endogenous H2O2 levels. To overcome these limitations, we therefore sought to develop an effective approach for the oxygen-independent treatment of hypoxic tumors. In this study, we designed a novel black phosphorus quantum dot (BPQD)/Escherichia coli (E. coli) hybrid system (BE) capable of facilitating the photothermal therapy (PTT) of hypoxic tumors. A simple electrostatic adsorption approach was used to conjugate BPQDs to E. coli. BE is capable of reliably targeting hypoxic tumors and mediating PTT. BPQDs in BE can directly facilitate X-ray-mediated radiosensitization of tumors, thereby achieving significant RT efficacy in response to lower doses of radiation, effectively and specifically damaging hypoxic tumor tissues to suppress the growth of tumors. Our results highlight this BE system as a novel approach to tumor radiosensitization with great potential for clinical application.

Photothermal and Enhanced Photocatalytic Therapies Conduce to Synergistic Anticancer Phototherapy with Biodegradable Titanium Diselenide Nanosheets.

Nanomaterial-based photothermal and photocatalytic therapies are effective against various types of cancers. However, combining two or more materials is considered necessary to achieve the synergistic anticancer effects of photothermal and photocatalytic therapy, which made the preparation process complicated. Herein, the authors describe simple 2D titanium diselenide (TiSe2 ) nanosheets (NSs) that can couple photothermal therapy with photocatalytic therapy. The TiSe2 NSs are prepared using a liquid exfoliation method. They show a layered structure and possess high photothermal conversion efficiency (65.58%) and good biocompatibility. Notably, upon near-infrared irradiation, these NSs exhibit good photocatalytic properties with enhanced reactive oxygen species generation and H2 O2 decomposition in vitro. They can also achieve high temperatures, with heat improving their catalytic ability to further amplify oxidative stress and glutathione depletion in cancer cells. Furthermore, molecular mechanism studies reveal that the synergistic effects of photothermal and enhanced photocatalytic therapy can simultaneously lead to apoptosis and necrosis in cancer cells via the HSP90/JAK3/NF-κB/IKB-α/Caspase-3 pathway. Systemic exploration reveals that the TiSe2 NSs has an appreciable degradation rate and accumulates passively in tumor tissue, where they facilitate photothermal and photocatalytic effects without obvious toxicity. Their study thus indicates the high potential of biodegradable TiSe2 NSs in synergistic phototherapy for cancer treatment.

Immunogenic exosome-encapsulated black phosphorus nanoparticles as an effective anticancer photo-nanovaccine.

Tumor vaccines are a promising form of cancer immunotherapy, but difficulties such as neo-antigen identification, activation of immune cells, and tumor infiltration prevent their clinical breakthrough. Interestingly, nanotechnology-based photothermal therapy (PTT) has great potential to overcome these barriers. Previous studies have shown that serum exosomes (hEX) from hyperthermia-treated tumor-bearing mice displayed an array of patient-specific tumor-associated antigens (TAAs), and strong immunoregulatory abilities in promoting dendritic cell (DC) differentiation and maturation. Here, we developed a tumor vaccine (hEX@BP) by encapsulating black phosphorus quantum dots (BPQDs) with exosomes (hEX) against a murine subcutaneous lung cancer model. In comparison with BPQDs alone (BP), hEX@BP demonstrated better long-term PTT performance, greater elevation of tumor temperature and tumor targeting efficacy in vivo. Vaccination with hEX@BP in combination with PTT further demonstrated an outstanding therapeutic efficacy against established lung cancer, and promoted the infiltration of T lymphocytes into the tumor tissue. Our findings demonstrated that hEX@BP might be an innovative cancer photo-nanovaccine that offers effective immuno-PTT against cancers.

Stellate Plasmonic Exosomes for Penetrative Targeting Tumor NIR-II Thermo-Radiotherapy.

Multifunctional gold (Au)-based nanomaterials with high atomic number (symbol Z) and strong absorbance in the second near-infrared window (NIR-II) property are emerging as promising candidates for tumor thermo-radiotherapy. The main limitations of applying Au-based nanomaterials to biomedical studies include the absence of active tumor-targeting ability, penetrating efficiency, and stability. In this study, we present a novel type of tumor cell-derived stellate plasmonic exosomes (TDSP-Exos) for penetrative targeted tumor NIR-II thermo-radiotherapy and photoacoustic imaging. The TDSP-Exos are abundantly and easily produced by the incubation of tumor cells with gold nanostars, based on which gold nanostars promote the exocytosis of exosomes from tumor cells. Compared with bare gold nanostars, the TDSP-Exos exhibit pronounced accumulation in deep tumor tissues and perform well in both PA imaging and NIR-II thermo-radiotherapy against the tumor. Moreover, the TDSP-Exos improve tumor hypoxia to enhanced radiotherapy by NIR-II photothermal therapy. This work indicates that the tumor cell-derived exosomes have the potential to function as a universal carrier of photothermal agents for targeted tumor NIR-II thermo-radiotherapy.

Emerging combination strategies with phototherapy in cancer nanomedicine.

Optical techniques using developed laser and optical devices have made a profound impact on modern medicine, with "biomedical optics" becoming an emerging field. Sophisticated technologies have been developed in cancer nanomedicine, such as photothermal therapy and photodynamic therapy, among others. However, single-mode phototherapy cannot completely treat persistent tumors, with the challenges of relapse or metastasis remaining; therefore, combinatorial strategies are being developed. In this review, the role of light in cancer therapy and the challenges of phototherapy are discussed. The development of combinatorial strategies with other therapeutic methods, including chemotherapy, immunotherapy, gene therapy, and radiotherapy, is presented and future directions are further discussed. This review aims to highlight the significance of light in cancer therapy and discuss the combinatorial strategies that show promise in addressing the challenges of phototherapy.

Bimetallic nanodots for tri-modal CT/MRI/PA imaging and hypoxia-resistant thermoradiotherapy in the NIR-II biological windows.

Hypoxic tumor microenvironment leads to resistance or failure of radiotherapy (RT). As a non-invasive therapy, photothermal therapy (PTT) can improve the tumor hypoxic microenvironment in addition to directly killing tumor cells. PTT combined with RT (thermoradiotherapy) becomes an emerging treatment. Multi-functional nanoparticles used for hypoxia-resistant thermoradiotherapy in the second near-infrared (NIR-II) biological windows (1000-1700 nm) are urgently needed to be developed. Here, a facil method synthesis of ultra-small cysteamine (Cys)-coated FePd bimetallic nanodots (NDs) is reported. These NDs can not only produce effective hyperthermia (35.4%) when irradiated in the NIR-II region (1064 nm) but also have an enhanced radiation effect due to i) Hypoxic improvement in tumor tissues by photothermal treatment in the NIR-II Biological Windows can greatly enhance the sensitivity of tumor cells to radiotherapy ii) The ability of NDs to deposit radiation energy in tumors has further enhanced the sensitivity of tumor cells to radiotherapy. Meanwhile, NDs was a contrast agent for tri-modal imaging including computed tomography (CT)/magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) in vitro and in vivo. Both in vitro and in vivo tests demonstrated good biocompatibility and excellent stability of NDs, indicating great potential for clinical applications.