Photoactivated Formation of an Extravascular Dynamic Hydrogel as an Intelligent Blood Flow Regulator to Reprogram the Immunogenic Landscape.

Long-term tumor starvation may be a potential strategy to elevate the antitumor immune response by depriving nutrients. However, combining long-term starvation therapy with immunotherapy often yields limited efficacy due to the blockage of immune cell migration pathways. Herein, an intelligent blood flow regulator (BFR) is first established through photoactivated in situ formation of the extravascular dynamic hydrogel to compress blood vessels, which can induce long-term tumor starvation to elicit metabolic stress in tumor cells without affecting immune cell migration pathways. By leveraging methacrylate-modified nanophotosensitizers (HMMAN) and biodegradable gelatin methacrylate (GelMA), the developed extravascular hydrogel dynamically regulates blood flow via enzymatic degradation. Additionally, aPD-L1 loaded into HMMAN continuously blocks immune checkpoints. Systematic in vivo experiments demonstrate that the combination of immune checkpoint blockade (ICB) and BFR-induced metabolic stress (BIMS) significantly delays the progression of Lewis lung and breast cancers by reshaping the tumor immunogenic landscape and enhancing antitumor immune responses.

Glucose-responsive enzymatic biomimetic nanodots for H2O2 self-supplied catalytic photothermal/chemodynamic anticancer therapy.

Photothermal therapy (PTT) combined with chemodynamic therapy (CDT) presents an appealing complementary anti-tumor strategy, wherein PTT accelerates the production of reactive oxygen species (ROS) in CDT and CDT eliminates residual tumor tissues that survive from PTT treatment. However, nanomaterials utilized in PTT/CDT are limited by non-specific damage to the entire organism. Herein, a glucose-responsive enzymatic Fe@HRP-ABTS/GOx nanodot is judiciously designed for tumor-specific PTT/CDT via a simple and clean protein-templated biomimetic mineralization synthesis. By oxidizing glucose in tumor cells, glucose oxidase (GOx) activates glucose-responsive tumor therapy and increases the concentration of H2O2 at the tumor site. More importantly, the self-supplied peroxide hydrogen (H2O2) can convert ABTS (2,2'-Hydrazine-bis(3-ethylbenzothiazoline-6-sulfonic acid) diamine salt) into oxidized ABTS (oxABTS) through horseradish peroxidase (HRP) catalysis for PTT and photoacoustic (PA) imaging. Furthermore, the Fe2+ arising from the reduction of Fe3+ by overexpressed GSH reacts with H2O2 to generate intensely reactive •OH through the Fenton reaction, concurrently depleting GSH and inducing efficient tumor CDT. The in vitro and in vivo experiments demonstrate superior cancer cell killing and tumor eradication effect of Fe@HRP-ABTS/GOx nanodot under near-infrared (NIR) laser irradiation. Collectively, the nanodots provide mutually reinforcing catalytic PTT/CDT anti-tumor strategies for treating liver cancer and potentially other malignancies. STATEMENT OF SIGNIFICANCE: Combinatorial antitumor therapy with nanomedicines presents great prospects for development. However, the limitation of non-specific damage to normal tissues hinders its further clinical application. In this work, we fabricated tumor-selective biomimetic Fe@HRP-ABTS/GOx nanodots for H2O2 self-supplied catalytic photothermal/chemodynamic therapy of tumors. The biomimetic synthesis strategy provides the nanodots with enzymatic activity in response to glucose to produce H2O2. The self-supplied H2O2 initiates photothermal therapy with oxidized ABTS and enhances chemodynamic therapy through simultaneous •OH generation and GSH depletion. Our work provides a new paradigm for developing tumor-selective catalytic nanomedicines and will guide further clinical translation of the enzymatic biomimetic synthesis strategy.

Enzymatic bionanocatalysts for combating peri-implant biofilm infections by specific heat-amplified chemodynamic therapy and innate immunomodulation.

Bacterial biofilm-associated infection is a life-threatening emergency contributing from drug resistance and immune escape. Herein, a novel non-antibiotic strategy based on the synergy of bionanocatalysts-driven heat-amplified chemodynamic therapy (CDT) and innate immunomodulation is proposed for specific biofilm elimination by the smart design of a biofilm microenvironment (BME)-responsive double-layered metal-organic framework (MOF) bionanocatalysts (MACG) composed of MIL-100 and CuBTC. Once reaching the acidic BME, the acidity-triggered degradation of CuBTC allows the sequential release of glucose oxidase (GOx) and an activable photothermal agent, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). GOx converts glucose into H2O2 and gluconic acid, which can further acidify the BME to accelerate the CuBTC degradation and GOx/ABTS release. The in vitro and in vivo results show that horseradish peroxidase (HRP)-mimicking MIL-100 in the presence of self-supplied H2O2 can catalyze the oxidation of ABTS into oxABTS to yield a photothermal effect that breaks the biofilm structure via eDNA damage. Simultaneously, the Cu ion released from the degraded CuBTC can deplete glutathione and catalyze the splitting of H2O2 into •OH, which can effectively penetrate the heat-induced loose biofilms and kill sessile bacteria (up to 98.64%), such as E. coli and MRSA. Particularly, MACG-stimulated M1-macrophage polarization suppresses the biofilm regeneration by secreting pro-inflammatory cytokines (e.g., IL-6, TNF-α, etc.) and forming a continuous pro-inflammatory microenvironment in peri-implant biofilm infection animals for at least 14 days. Such BME-responsive strategy has the promise to precisely eliminate refractory peri-implant biofilm infections with extremely few adverse effects.

Bioresponsive nano-antibacterials for H2S-sensitized hyperthermia and immunomodulation against refractory implant-related infections.

There is an increasingly growing demand for nonantibiotic strategies to overcome drug resistance in bacterial biofilm infections. Here, a novel "gas-sensitized hyperthermia" strategy is proposed for appreciable bacteria killing by the smart design of a metal-organic framework (MOF)-sealed Prussian blue-based nanocarrier (MSDG). Once the biofilm microenvironment (BME) is reached, the acidity-activated MOF degradation allows the release of diallyl trisulfide and subsequent glutathione-responsive generation of hydrogen sulfide (H2S) gas. Upon near-infrared irradiation, H2S-sensitized hyperthermia arising from MSDG can efficiently eliminate biofilms through H2S-induced extracellular DNA damage and heat-induced bacterial death. The generated H2S in the biofilm can stimulate the polarization of macrophages toward M2 phenotype for reshaping immune microenvironment. Subsequently, the secretion of abundant regeneration-related cytokines from M2 macrophages accelerates tissue regeneration by reversing the infection-induced pro-inflammatory environment in an implant-related infection model. Collectively, such BME-responsive nano-antibacterials can achieve biofilm-specific H2S-sensitized thermal eradiation and immunomodulatory tissue remodeling, thus realizing the renaissance of precision treatment of refractory implant-related infections.