Tumor hypoxia is the pivotal factor limiting the therapeutic efficacy of photodynamic therapy (PDT), and can be partly improved by either the oxygen economizing or the oxygen supplementation strategies. Nevertheless, the current studies scarcely integrated the merits of both strategies and neglected the bottleneck of poor oxygen infiltration in deep tumors, resulting in PDT resistance. Herein, we developed an oxygen reservoir-irrigated PDT which integrates oxygen supply, oxygen economizing, and oxygen infiltration altogether. Specifically, mitochondria-targeted mesoporous prussian blue nanoparticles (Ce6@TPB) were fabricated to bridge the gap between oxygen economizing and oxygen supplementation by reducing oxygen output while increasing oxygen input. Hyaluronidase-loaded microneedles were further developed to pave the way for deep PDT with increased infusion of oxygen and photosensitizer by degrading dense extracellular matrix. The modulation of tumor oxygenation and permeability during PDT leads to the complete eradication of primary melanoma and strong immunogenic cell death. Its further combination with checkpoint-blockade inhibitor greatly suppressed the proliferation of distal tumors by reprogramming immune microenvironments, as evidenced by the depletion of M2 macrophage, increased infiltration of anti-tumor immune cells, and elevated excretion of immune cytokines. Therefore, such an oxygen reservoir-irrigated PDT potentiates powerful photoimmunotherapy and provides a favorable prospect for tumor treatment.

Rapid evolution of multidrug resistance in bacterial pathogens is outpacing the development of new antibiotics, and chemodynamic therapy (CDT) provides an excellent alternative. However, achieving highly efficient CDT is still a great challenge, since the pH in the infection site is close to neutral and the supply of H₂O₂ is inadequate. We herein constructed the antibacterial nanoreactors. Indocyanine green (ICG) and glucose oxidase (GOx) were incorporated into homologous zeolitic imidazolate framework-8 (ZIF-8) nanoparticles coating with metal polyphenol network (MPN) composed by Fe³⁺ and tannic acid (TA). The well-designed nanoreactors could simultaneously break the pH and H₂O₂ limitations, and generate hyperthermia under irradiation, thus realizing a triple-enhanced CDT for high-efficiency sterilization. Furthermore, the nanoreactors could combine CDT with photothermal therapy (PTT) and photodynamic therapy (PDT), which not only improved the bactericidal efficiency and broadened the antibacterial spectrum, but also alleviated the antibiotics resistance issues. Remarkably, the proposed nanoreactors achieved a robust in vitro bacterial killing against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative Pseudomonas aeruginosa. The nanoreactors achieved an 99.7% MRSA reduction in an MRSA-induced murine abscess model accompanied with negligible toxicity. Overall, this study provides a promising strategy for multiple-enhanced CDT and multimodal combined therapy for pathogenic infections.

Nanomedicine with high specificity has been a promising tool for cancer diagnosis and therapy. However, the successful application of nanoparticle-based superficial cancer therapy is severely hindered by restricted deep tumor tissue accumulation and penetration. Herein, a self-assembly nanomicelle dissolving microneedle (DMN) patch according to the “nano in micro” strategy was conducted to co-deliver a first-line chemotherapeutic agent paclitaxel (PTX), and a photosensitizer IR780 (PTX/IR780-NMs @DMNs) for chemo-photothermal synergetic melanoma therapy. Upon direct insertion into the tumor site, DMNs created a regular and multipoint three-dimensional drug depot to maximize the tumor accumulation. Accompanied by the DMN dissolution, the composition of the needle matrixes self-assembled into nanomicelles, which could efficiently penetrate deep tumor tissue. Upon laser irradiation, the nanomicelles could not only ablate tumor cells directly by photothermal conversion but also trigger PTX release to induce tumor cell apoptosis. In vivo results showed that compared with intravenous injection, IR780 delivered by PTX/IR780-NMs @DMNs was almost completely accumulated at the tumor site. The antitumor results revealed that the PTX/IR780-NMs @DMNs could effectively eliminate tumors with an 88% curable rate without any damage to normal tissues. This work provides a versatile and generalizable framework for designing self-assembly DMN-mediated combination therapy to fight against superficial cancer.