Diabetic chronic wounds present formidable clinical challenges due to a vicious cycle of methicillin-resistant Staphylococcus aureus (MRSA) infections, persistent hypoxia, and chronic inflammation. We herein report a sprayable and rapidly photo-cross-linkable hydrogel (LMG@GH-MA) that integrates a specially engineered microwave (MW)-responsive luteolin-based nanozyme (Lut-Mn/MnO2) with glucose oxidase (GOx). The rational design features a notable Mn4+/Mn3+ mixed-valence state in the nanozyme, which not only exhibits superior multienzyme-like activities but also serves as a robust MW susceptor, converting electromagnetic energy into localized mild hyperthermia (40.4 °C). This thermal activation enables self-amplifying catalytic cascade, where heat-enhanced GOx consumes wound glucose to produce H2O2, which is then efficiently converted into therapeutic oxygen by the heat-augmented Lut-Mn/MnO2, thereby synchronously alleviating hyperglycemia and hypoxia. Furthermore, the system achieves potent antibiotic-free antibacterial efficacy (99.19% ± 0.14%) against MRSA through a combined assault of physical membrane disruption and profound metabolic interference. The MRSA-infected diabetic rat model confirms superior therapeutic outcomes, including near-complete wound closure by Day 12, effective MRSA clearance, and reduced inflammation. Crucially, we provide strong functional evidence that LMG@GH-MA actively remodels the immune microenvironment by suppressing key pro-inflammatory pathways (e.g., IL-17, TNF-α), thereby shifting the wound milieu from a chronic inflammatory state to a pro-regenerative one. Our work integrates an approach that merges advanced nanotechnology with accessible physical stimuli, offering a promising strategy that warrants further investigation for intractable diabetic wound regeneration.

Mitochondrial or lysosomal damage is the initial step of apoptosis, and detecting their damaging sequences is crucial for understanding programmed cell death and related diseases. However, fluorescent probes capable of reporting their damaging order are rarely reported, owing to the deficiency of valid strategies. Herein, by rationally modifying targeting groups and employing a side-chain regulation strategy, a probe Trav was designed to detect the temporal order of lysosomal and mitochondrial damage. Trav targeted both mitochondria and lysosomes in living cells and distinguished them from each other with different fluorescence colors. Upon mitochondrial damage, Trav translocated to lysosomes, accompanied by a fluorescence color change. Subsequently, after lysosomal damage, Trav was relocated to the nucleus and emitted a third color. Similarly, if lysosomal damage occurs first, Trav migrates to mitochondria, which relocated into the nucleus after subsequent mitochondrial damage. Thus, Trav enabled reporting the damaging order of mitochondria and lysosomes through subcellular translocation and fluorescence color changes. Using Trav, we successfully revealed that in hyperthermia-induced injury lysosomal damage preceded mitochondrial damage, and this process was associated with increased levels of reactive oxygen species. Reducing agents, such as cysteine, can inhibit the injury. Trav holds promise as a valuable molecular tool for advancing research in related biomedical fields.

Nanoparticles (NPs) based on holmium or holmium-doped have attracted increasing attention in biomedicine, addressing the needs in cancer diagnostics and therapy due to their unique magnetic and optical properties. However, there are only a few comprehensive reviews addressing fabrication approaches and multifunctional applications. This paper focuses on holmium-based nanostructures, with a particular emphasis on Ho-doped superparamagnetic iron oxide nanoparticles (Ho-doped SPIONs), and their potential for targeted therapies. Both, holmium-doped and holmium-based nanoparticles offer their potential to enhance drug delivery through controllable size, surface modifications, and controlled release mechanisms, as well as use of them as β[-] emitters, an alternative to the conventional radiotherapy. However, optimization of the experimental conditions during synthesis is also crucial to safety in clinical use. This work reviews (1) the design of Ho-based NPs including Ho-doped SPIONs for theranostic applications, including (2) magnetic hyperthermia, (3) drug delivery, and (4) radiolabeling. It also highlights the current lack of data for Ho-doped SPIONs in (5) the near-infrared range and (6) magnetic resonance imaging, while discussing other Ho-based nanostructures reported in the literature. Additionally, this review paper shows limitations and future perspectives for clinical translation.

The clinical treatment of chronically infected wounds faces multiple challenges, including antibiotic resistance, imprecise thermal control, and frequent dressing changes that hinder healing. Herein, we developed a multifunctional mild hyperthermic microneedle patch (GPD-NAS@PDA MN) based on the reversible phase-transition characteristics of lower critical solution temperature (LCST) thermoresponsive polymers, enabling single-application administration and precise long-term temperature regulation. Under near-infrared irradiation (NIR), the backing layer can actively protect surrounding normal tissues while efficiently killing bacteria and eradicating biofilms, thereby reducing reliance on antimicrobial agents. The needle tip continuously releases the angiogenic drug deferoxamine mesylate (DFO) via a stable network structure, synergistically promoting angiogenesis and tissue repair through photothermal effects. Transcriptomic analysis reveals that this system can regulate pathways related to oxidative stress and metabolic networks. In vivo studies confirm that the wound healing rate of the GPD-NAS@PDA MN is as high as 93.55% on the 14th day after a single application, thereby avoiding secondary tissue damage. In summary, the multifunctional microneedle system integrates precise hyperthermia, potent antibacterial and anti-biofilm activity, and anti-inflammatory and pro-angiogenic functions, avoiding the complexity of multiple drug combinations and frequent dressing changes in traditional therapies and providing a promising personalized strategy for chronic wound management.

Despite advances in combined photothermal (PTT) and photodynamic (PDT) therapy for melanoma, therapeutic efficacy remains limited by tumor hypoxia, intracellular glutathione (GSH), insufficient tumor targeting, and photobleaching of photosensitizers. Herein, tumor-targeting and GSH self-depleting hyaluronic acid (HA)/tannic acid (TA)-engineered Prussian blue (PB) oxygen nanogenerators (ONs) loaded with IR780 (IHTPB ONs) are developed to enhance synergistic PTT/PDT. The IHTPB ONs exhibit uniform morphology, excellent colloidal stability, acidity/GSH-responsive IR780 release, high photothermal conversion efficiency (60%), and outstanding photothermal stability. Importantly, PB-mediated GSH oxidation and TA-mediated GSH conjugation enable dual-mode GSH depletion, while PB catalyzes oxygen generation to alleviate tumor hypoxia and promote IR780-mediated singlet oxygen production. Following CD44-mediated cellular uptake, IHTPB ONs effectively deplete intracellular GSH and, under near-infrared irradiation, induce robust reactive oxygen species generation and hyperthermia, leading to mitochondrial dysfunction, lipid peroxidation, apoptosis, and ferroptosis. In vivo, IHTPB ONs exhibit superior tumor accumulation and significantly enhanced antitumor efficacy compared with free IR780 and non-targeted nanoparticles, resulting in prolonged survival of melanoma-bearing mice. This work provides an effective nanoplatform integrating tumor targeting, oxygen self-supply, and dual-mode GSH depletion to potentiate synergistic PTT/PDT for melanoma therapy.

Local hyperthermia is an effective treatment for advanced malignant tumors, whose multilayer structure and physiological heterogeneity strongly influence their response to therapy. In this work, a generalized multilayer reaction-diffusion model is developed to study tumor-volume dynamics under localized hyperthermic treatment. The tumor is represented as a set of interacting biological layers, allowing spatial variation in key parameters such as diffusion and proliferation. The model is formulated with appropriate initial, interface and boundary conditions and solved using the finite element method. Simulations are carried out for planar, cylindrical and spherical tumor geometries to examine the effects of heterogeneity, geometry and hyperthermia. The results show a clear reduction in tumor volume under thermal therapy, with stronger effects observed in spherical tumors due to enhanced diffusion. Sensitivity analysis and comparison with published data further support the reliability of the model. Overall, the proposed work provides a simple and flexible approach for analyzing tumor behavior under hyperthermic treatment. This work can support future treatment planning studies.

Magnetic particle imaging (MPI) and magnetic hyperthermia therapy (MHT) both rely strongly on the dynamic magnetic response of magnetic nanoparticles (MNPs), yet the particle design requirements for achieving strong imaging contrast and efficient heating are not always aligned. Here, we systematically investigate the effects of core size and PEG surface coating on the dual MPI-MHT performance of iron oxide MNPs. Six formulations with core sizes of 10, 20, and 30 nm, either uncoated Fe3O4 or PEG-coated Fe3O4 (Fe3O4@PEG), were systematically evaluated. MPI performance was assessed using magnetic particle spectroscopy (MPS) under an excitation field of 10 mT at 7.7 and 11.4 kHz. Harmonic analysis revealed that 20 nm Fe3O4@PEG nanoparticles generated the strongest MPI response, characterized by enhanced higher-order harmonic magnitudes and slower harmonic decay. MHT performance was then evaluated under various alternating magnetic field (AMF) conditions: 30 mT at 101.5 kHz, 15 mT at 434.4 kHz, 25 mT at 252.5 kHz, and 10 mT at 951.8 kHz. Results demonstrate that 20 nm Fe3O4@PEG nanoparticles also showed superior heating efficiency, especially under low-field, high-frequency excitation. These findings suggest that a 20 nm core size, combined with a PEG coating, provides an optimal balance between rapid magnetic response, colloidal stability, and energy dissipation. Furthermore, colloidal stability over seven days and cell viability assays confirm that the MNPs are colloidally stable and that 20 and 30 nm MNPs are biocompatible under the tested conditions for up to 48 h. This study provides a rational design framework for developing dual-functional iron oxide nanoparticles for image-guided magnetic hyperthermia and other integrated diagnostic-therapeutic biomedical applications.

This study presents an experimentally validated dual-band focused microwave thermotherapy (FMT) system capable of operating at both 100 MHz and 434 MHz within a single phased-array platform. The proposed system features a dual-band applicator array designed to support resonant operation at widely separated frequencies, thereby enabling the treatment of tumors varying in depth and size without the need for hardware modification. A time-reversal (TR) based excitation method was employed to determine the optimal phase and amplitude weights for each channel. Experimental phantom measurements demonstrated accurate field convergence at both frequencies, with focal spot sizes and positioning errors consistent with fundamental electromagnetic diffraction limits. Specifically, the 100 MHz band produced a broad focal region suitable for deep-seated targets, whereas the 434 MHz band generated a compact focus appropriate for high-resolution targeting at shallower depths. These results indicate that the proposed dual-band system offers enhanced adaptability compared to conventional single-band hyperthermia devices, providing a promising platform for future patient-specific cancer treatment.

Quaternary ammonium compounds (QACs) hold great promise as alternatives to conventional antibiotics due to their broad-spectrum antibacterial activity and minimal propensity for inducing bacterial drug resistance. However, their inherent cytotoxicity and pro-inflammatory property perpetuate an intractable efficacy-biocompatibility trade-off, severely limiting clinical translation. Herein, aimed to solve this dilemma, we developed a microwave-responsive ionic liquid (IL) via the integration of QACs with an anti-inflammatory anionic organic compound, enabling synergistic bactericidal efficacy through microwave-induced hyperthermia while concomitantly alleviating QAC-related toxicity and inflammation. After loading into bacteria-targeted hollow polydopamine nanoparticles (HPDA NPs), this IL-based nanoplatform exhibited selective biocidal discrimination between bacterial and mammalian cells, fundamentally mitigating QAC-related cytotoxicity. Notably, embedding these nanoparticles into poly (vinyl pyrrolidone) MNs (IL@HPDA@MN) achieved up to 99.8% bactericidal efficiency coupled with robust anti-inflammatory effects in a mouse subcutaneous abscess model, leading to accelerated abscess resolution and tissue regeneration that outperformed clinical antibiotics. Beyond resolving the QAC-centric efficacy-biocompatibility paradox, this work provides a generalizable framework for engineering toxic cationic antibacterial agents into biocompatible, targeted therapeutics, offering a transformative approach for treating deep-seated bacterial infections that are refractory to traditional therapies. STATEMENT OF SIGNIFICANCE: Quaternary ammonium compounds (QACs) are promising alternatives to conventional antibiotics due to their broad-spectrum activity and low resistance risk. Yet, their clinical adoption remains paralyzed by an inherent trade-off between bactericidal efficacy and unacceptable cytotoxicity, pro-inflammation. Here, we break this deadlock by rationally integrating a QAC with an anti‑inflammatory organic compound to form a microwave-responsive ionic liquid (IL). When encapsulated in bacteria-targeted hollow polydopamine nanoparticles and further loaded into a dissolvable microneedle patch, this IL-based platform achieves potent bacterial killing under mild microwave irradiation while exhibiting negligible toxicity toward mammalian cells. In a murine subcutaneous abscess model, the system rapidly resolves deep-seated infections and curtails local inflammation, achieving therapeutic outcomes that rival or surpass those of clinical antibiotics. Beyond offering a ready-to-use strategy for treating refractory deep-tissue infections, this work establishes a generalizable paradigm for converting toxic cationic antimicrobials into biocompatible, spatially controllable therapeutics.

Postoperative recurrence and metastasis remain critical obstacles in uveal melanoma treatment. Herein, we report the synthesis of a hierarchical drug-releasing nanocomposite hydrogel (LAP NPs/ICG gel) via in situ crosslinking of chitosan, co-encapsulating indocyanine green and hyaluronic acid-based lapatinib-loaded nanoparticles (LAP NPs) for postoperative synergistic chemo-photothermal therapy of uveal melanoma. The LAP NPs/ICG gel can be injected into the tumor resection cavity and remains in vivo for more than four weeks. Under near-infrared irradiation, the hydrogel induces rapid local hyperthermia to ablate residual tumor tissue. Concurrently, progressive hydrogel degradation enables sustained release of LAP NPs, which actively target disseminated malignant lesions, enhance tumor penetration and intratumoral retention, ultimately triggering glutathione-responsive intracellular drug release for efficient tumor eradication. In vitro and in vivo studies using MuM-2B tumor models demonstrate that a single local injection of the LAP NPs/ICG gel significantly suppresses tumor growth, postoperative recurrence, and hepatic metastasis. Moreover, the hydrogel-based therapeutic system shows no detectable damage to adjacent healthy tissues or major organs, ensuring a favorable in vivo safety profile. Overall, this multimodal hydrogel system represents a promising adjunctive strategy for postoperative uveal melanoma therapy.

Myocardial infarction (MI) disrupts myocardial electrical conduction and contractile function, causing irreversible cardiac dysfunction. Piezoelectric materials offer great potential for MI repair via in situ electrical generation. However, traditional ultrasound-triggered piezoelectric activation inevitably induces local hyperthermia and secondary myocardial damage. Additionally, the piezoelectric therapeutic mechanisms for cardiac therapy remain poorly understood. Herein, we innovatively fabricated a magneto-responsive, self-powered CoFe2O4-PVDF composite therapeutic system. This composite achieves on-demand electrical modulation via non-invasive magnetic stimulation: CoFe2O4 generates magnetostrictive strain under magnetic actuation, which is efficiently converted into functional piezoelectric charges by PVDF, thereby enabling safe, spatiotemporally controllable in situ cardiac electrical stimulation. In vivo results confirmed that the system significantly improved cardiac ejection fraction and reduced myocardial fibrosis. It upregulated key genes governing angiogenesis, calcium signaling, and cardiomyocyte proliferation. In vitro, the composite promoted hypoxic H9c2 cardiomyocyte spreading and suppressed apoptosis under magnetic stimulation. First-principles calculations further verified that CoFe2O4 optimizes the electronic state density of PVDF and enhances its charge output, revealing the synergistic mechanism. This work establishes an innovative magneto-driven, on-demand electrical therapy platform to overcome the limitations of conventional piezoelectric treatment. It provides novel mechanistic insights and a translational strategy for efficient MI repair via precise in situ regulation of the myocardial electrical microenvironment.

Metabolic reprogramming is a hallmark of malignant tumors, providing tumor cells with energy and promoting immune escape through changes in glucose, lipid, and amino acid metabolism. Photothermal therapy (PTT) not only eliminates tumor cells through localized hyperthermia but also disrupts metabolic networks. However, the mechanisms by which PTT-induced metabolic perturbation engages antitumor immunity remain a considerable challenge. This review proposes that PTT interferes with tumor metabolism through organelle stress and synergizes with exogenous drugs to enhance metabolic perturbation, thereby eliciting a potent antitumor immune response. We first detail how hyperthermia and ROS induced by PTT damage organelles, leading to organelle stress, including mitochondrial depolarization, endoplasmic reticulum (ER) proteotoxicity, cytosolic enzyme denaturation, and nucleolar stress. Critically, stressed organelles release immunogenic signals, activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to trigger innate immune recognition, and regulating the functions of CD8[+] T cells and macrophages through metabolites in the tumor microenvironment (TME). We also discuss how tumor cells activate adaptive responses, such as heat shock protein (HSP) upregulation and metabolic switching, to resist sublethal thermal stress, and evaluate synergistic strategies designed to amplify organelle stress and overcome thermotolerance. Finally, we focus on the latest advancements in overcoming tumor heterogeneity and advancing the clinical translation of targeted organelle PTT nanoplatforms. It is expected to elucidate the mechanism by which organelle stress in PTT causes metabolic perturbation, the tumor adaptive response, and its impact on tumor immunity, providing innovative ideas and references for the development of metabolic and tumor combined treatment strategies based on PTT.