Global aging heightens the risk of oral disorders, among which periodontitis is the major cause of tooth loss in the aging population. The regeneration of damaged periodontal hard tissue is highly challenging due to the existence of the refractory local inflammation. Owing to the potent anti-inflammatory capabilities, regulatory T cells hold great promise in immunotherapies for tissue regeneration. However, the transferred regulatory T cells can alter their phenotypes and functions in local inflammatory milieu, significantly impairing their therapeutic efficacy. Herein, we introduce a novel regulatory T cell-based nanobiohybrid system bearing polyphenol-functionalized rapamycin nanocomplexes. The sustained in situ release of immunosuppressant rapamycin from the cell-attached nanocomplexes maintains the anti-inflammatory phenotype of regulatory T cells in the inflammatory milieu. The synergistic actions of the anti-inflammatory cytokines secreted and the immunosuppressant released guide a pro-resolving polarization of macrophages and enhance osteogenic differentiation of bone marrow-derived stromal cells. The stabilized phenotype of the regulatory T cells dramatically promoted the resolution of periodontal inflammation and the repair of the hard tissue (alveolar bone) in vivo. Overall, these studies highlight a potent regulatory T cell-based nanobiohybrid therapy to treat periodontitis by modulating periodontal immune microenvironment.

Increasing evidence has showed that tumorigenesis is closely linked to inflammation, regulated by multiple signaling pathways. Among these, the cyclooxygenase-2/prostaglandin E (COX-2/PGE) axis plays a crucial role in the progression of both inflammation and cancer. Inhibiting the activity of COX-2 can reduce PGE secretion, thereby suppressing tumor growth. Therefore, COX-2 inhibitors are considered potential therapeutic agents for cancers. However, their clinical applications are greatly hindered by poor physicochemical properties and serious adverse effects. Fortunately, the advent of nanotechnology offers solutions to these limitations, enhancing drug delivery efficiency and mitigating adverse effects. Given the considerable progress in this area, it is timely to review emerging COX-2 inhibitors-based nanotherapeutics for cancer diagnosis and therapy. In this review, we first outline the various antineoplastic mechanisms of COX-2 inhibitors, then comprehensively summarize COX-2 inhibitors-based nanotherapeutics for cancer monotherapy, combination therapy, and diagnosis. Finally, we highlight and discuss future perspectives and challenges in the development of COX-2 inhibitors-based nanomedicine.

Pyroptosis is considered as a new way to effectively boost the immune response of tumors and inhibit tumor growth. Effective strategies to induce pyroptosis mainly rely on chemotherapeutic drugs and phototherapy, but their potential biotoxicity and phototoxicity limit their application in biomedicine. Herein, we designed a NIR-II emitting pyroptosis biotuner, Rd-TTPA, which induced pyroptosis under ultrasound irradiation to achieve pyroptosis-enhanced sonodynamic therapy (SDT) and immunogenic cell death (ICD) for tumors. Benefiting from its A-π-D-D structure enhanced donor-acceptor interaction, Rd-TTPA can induce cell pyroptosis under both normoxia (21 % O) and hypoxia (2 % O) conditions by rapidly generating superoxide radicals (O) upon ultrasound irradiation. The sonodynamic biotuner of pyroptosis overcomes the longstanding weakness of chemical drug and photosensitizer-based pyroptosis, such as drug resistance and limited penetration depth. In-depth studies demonstrated that Rd-TTPA can selectively target tumor cell mitochondria and possess excellent in vivo NIR-II fluorescence imaging capabilities. Administrating a tumor-bearing mouse model with Rd-TPPA, satisfying antitumor efficacy via pyroptosis-augmented SDT was achieved upon the guidance of NIR-II fluorescence imaging.

The frequent immune escape of tumor cells and fluctuating therapeutic efficiency vary with each individual are two critical issues for immunotherapy against malignant tumor. Herein, we fabricated an intelligent core-shell nanoparticle (SNAs@CCM) to significantly inhibit the PD-1/PD-L1 mediated immune escape by on-demand regulation of various oncogenic microRNAs and perform RNAs dependent photothermal-immunotherapy to achieve precise and efficient treatment meeting the individual requirements of specific patients by in situ generation of customized tumor-associated antigens. The SNAs@CCM consisted of antisense oligonucleotides grafted gold nanoparticles (SNAs) as core and TLR7 agonist imiquimod (R837) functionalized cancer cell membrane (CCM) as shell, in which the acid-labile Schiff base bond was used to connect the R837 and CCM. During therapy, the acid environment of tumor tissue cleaved the Schiff base to generate free R837 and SNAs@CCM. The SNAs@CCM further entered tumor cells via CCM mediated internalization, and then specifically hybridized with over-expressed miR-130a and miR-21, resulting in effective inhibition of the migration and PD-L1 expression of tumor cells to avoid their immune escape. Meanwhile, the RNAs capture also caused significant aggregation of SNAs, which immediately generated photothermal agents within tumor cells to perform highly selective photothermal therapy under NIR irradiation. These chain processes not only damaged the primary tumor, but also produced plenty of tumor-associated antigens, which matured the surrounding dendritic cells (DCs) and activated anti-tumor T cells along with the released R837, resulting in the enhanced immunotherapy with suppressive immune escape. Both in vivo and in vitro experiments demonstrated that our nanoparticles were able to inhibit primary tumor and its metastasis via multi-regulation of carcinogenic microRNAs and RNAs dependent photothermal-immune activations, which provided a promising strategy to reprogram the immunosuppressive microenvironment in tumor tissue for better malignant tumor therapy.

Brain stimulation has been recognized as a clinically effective strategy for treating neurological disorders. Endogenous brain neural precursor cells (NPCs) have been shown to be electrosensitive cells that respond to electrical stimulation by expanding in number, undergoing directed cathodal migration, and differentiating into neural phenotypes in vivo, supporting the application of electrical stimulation to promote neural repair. In this study, we present the design of a flexible and biodegradable brain stimulation electrode for temporally regulated neuromodulation of NPCs. Leveraging the cathodally skewed electrochemical window of molybdenum and the volumetric charge transfer properties of conductive polymer, we engineered the electrodes with high charge injection capacity for the delivery of biphasic monopolar stimulation. We demonstrate that the electrodes are biocompatible and can deliver an electric field sufficient for NPC activation for 7 days post implantation before undergoing resorption in physiological conditions, thereby eliminating the need for surgical extraction. The biodegradable electrode demonstrated its potential to be used for NPC-based neural repair strategies.

The clinical treatment of osteosarcoma faces great challenges of residual tumor cells leading to tumor recurrence and irregular bone defects difficult to repair after surgery removal of the primary tumor tissue. We developed an injectable and in-situ cross-linkable hydrogel (named MOG hydrogel) using MgO nanoparticles and dopamine-conjugated gelatin as main components. MgO was rationally designed as a multifunctional active ingredient to mediate in situ gelation, tumor therapy, and bone repair sequentially. The 10MOG (with 10 mg/mL MgO content) showed excellent gel stability, injectability, shape adaptability, tissue adhesion, and rapid hemostatic ability. Importantly, 10MOG exhibited ideal sequential HO and Mg release property. The released HO synergized with photothermal therapy for enhanced tumor recurrence suppression, and the sustainable Mg release efficiently promoted bone regeneration. The MOG hydrogel, possessing excellent on-demand antitumor and osteogenic capabilities in vitro and in vivo, exhibited tremendous potential in the clinical application for challenging postsurgical osteosarcoma treatment.

Abnormal tumor metabolism leads to tumor growth, metastasis, and recurrence, reprogramming tumor metabolism and activating potent anti-tumor immune response have been demonstrated to have good therapeutic effects on tumor elimination. Copper-based nanomaterials involved in cuproptosis show great prospects in these two aspects, but their efficiency is restricted by Cu homeostasis and the toxicity of the chelator. Here, the pH-responsive AuNRs@CuO core-shell plasmonic hybrid nanorods (ACNRs) have been successfully fabricated to realize microenvironment-controlled release at the tumor site for the combined therapy of cuproptosis and photothermal treatment. The AuNRs core exhibited excellent NIR-II photothermal property, which boost the intracellular concentration of copper to trigger severe cuproptosis and induce immunogenic cell death of tumor cells. In vivo studies demonstrated the ACNR exhibited efficient tumor therapy for primary, metastatic, and recurrent tumors. ACNRs-induced cuproptosis and PTT were capable of reprogramming energy metabolism, leading to a decreased production of lactic acid. This potential of metabolic reprogramming assisted in reshaping the immunosuppressive tumor microenvironment to facilitate the infiltration of immune cells and boost the immune responses triggered by PTT. The therapeutic mechanism was further verified by metabolomics analysis, which indicated that ACNRs + PTT treatment led to the inhibition of the Pentose Phosphate Pathway and Glycolysis pathways in tumor cells. The suppression of glycolytic reduced ATP synthesis, thereby hindering energy-dependent copper efflux, which in turn promoted cuproptosis. Taken together, this study offers promising insights for cuproptosis-based cancer treatment and sheds new light on nanomedicine-mediated metabolic modulation for future tumor therapy.

Integration of neural interfaces with minimal tissue disruption in the brain is ideal to develop robust tools that can address essential neuroscience questions and combat neurological disorders. However, implantation of intracortical devices provokes severe tissue inflammation within the brain, which requires a high metabolic demand to support a complex series of cellular events mediating tissue degeneration and wound healing. Pericytes, peri-vascular cells involved in blood-brain barrier maintenance, vascular permeability, waste clearance, and angiogenesis, have recently been implicated as potential perpetuators of neurodegeneration in brain injury and disease. While the intimate relationship between pericytes and the cortical microvasculature have been explored in other disease states, their behavior following microelectrode implantation, which is responsible for direct blood vessel disruption and dysfunction, is currently unknown. Using two-photon microscopy we observed dynamic changes in the structure and function of pericytes during implantation of a microelectrode array over a 4-week implantation period. Pericytes respond to electrode insertion through transient increases in intracellular calcium and underlying constriction of capillary vessels. Within days following the initial insertion, we observed an influx of new, proliferating pericytes which contribute to new blood vessel formation. Additionally, we discovered a potentially novel population of reactive immune cells in close proximity to the electrode-tissue interface actively engaging in encapsulation of the microelectrode array. Finally, we determined that intracellular pericyte calcium can be modulated by intracortical microstimulation in an amplitude- and frequency-dependent manner. This study provides a new perspective on the complex biological sequelae occurring at the electrode-tissue interface and will foster new avenues of potential research consideration and lead to development of more advanced therapeutic interventions towards improving the biocompatibility of neural electrode technology.

Effective, user-friendly, lifestyle-compatible, and economic treatment for type 2 diabetes (T2D) is urgently needed due to its high incidence and health threats. Here, we remolded Lactococcus lactis through genetic engineering to persistently secrete glucagon-like peptide-1 (L. lactis-GLP-1) and subsequent bioorthogonal arming with dopamine (DA)-based "gripper" and β-glucan (GN)-based "shield" (L. lactis-GLP-1-DA@GN) for treatment of T2D mice via oral administration. With protection by GN-based "shield", L. lactis-GLP-1-DA@GN achieved an impressive enhancement of survival by 20666 times compared with bare L. lactis-GLP-1 after experiencing gastrointestinal conditions and DA-based "gripper" was shielded from interaction with the upper digestive tract. Once prebiotic GN was metabolized by gut microbiota into short-chain fatty acids (SCFAs), underlying DA-based "gripper" was exposed to assist intestinal colonization of L. lactis-GLP-1, achieving synergistic treatment effects through secreted GLP-1 and SCFAs. With all advances, oral administration of L. lactis-GLP-1-DA@GN realized effective T2D treatment through improving glucose/lipid homeostasis, repairing major organs' damages, and positively modulating gut microbiota. Moreover, multi-omics analysis revealed that L. lactis-GLP-1-DA@GN also mainly intervened in liver's signaling pathways regarding lipid metabolism and oxidative regulation to advance anti-T2D process. Our strategy marks reconstruction of probiotics by combining chemical and biological tools, broadening the avenue of manipulating probiotics for disease treatments.

Orthodontic relapse is one of the most prevalent concerns of orthodontic therapy. Relapse results in patients' teeth reverting towards their pretreatment positions, which increases the susceptibility to functional problems, dental disease, and substantially increases the financial burden for retreatment. This phenomenon is thought to be induced by rapid remodeling of the periodontal ligament (PDL) in the early stages and poor bone quality in the later stages. Current therapies including fixed or removable retainers and fiberotomies have limitations with patient compliance and invasiveness. Approaches using biocompatible biomaterials, such as calcium phosphate polymer-induced liquid precursors (PILP), are an ideal translational approach for minimizing orthodontic relapse. Here, post-orthodontic relapse is reduced after a single injection of high concentration PILP (HC-PILP) nanoclusters by altering PDL remodeling in the early stage of relapse and improving trabecular bone quality in the later stage. HC-PILP nanoclusters are achieved by using high molecular weight poly aspartic acid (PASP, 14 kDa) and poly acrylic acid (PAA, 450 kDa), which resulted in a stable solution of high calcium and phosphate concentrations without premature precipitation. In vitro results show that HC-PILP nanoclusters prevented collagen type-I mineralization, which is essential for the tooth-PDL-bone interphase. In vivo experiments show that the HC-PILP nanoclusters minimize relapse and improve the trabecular bone quality in the late stages of relapse. Interestingly, HC-PILP nanoclusters also altered the remodeling of the PDL collagen during the early stages of relapse. Further in vitro experiments showed that HC-PILP nanoclusters alter the fibrillogenesis of collagen type-I by impacting the protein secondary structure and forming aggregates. These findings propose a new approach for treating orthodontic relapse and provide additional insight into the PILP nanocluster's structure and properties on collagenous structure repair.

Tissue repair is a highly regulated process involving immune, stromal, vascular, and parenchymal cell responses. Mediators of cellular responses at different phases of the healing process stimulate transitions through the continuum of repair. Histamine is an early mediator of healing, which, in skin, is released by resident cells (e.g., mast cells) after cutaneous injury, and acts to stimulate diverse responses in multiple cell populations. Histamine signaling is regulated by four distinct cell surface G-protein coupled receptors (HRH1-4 in humans, Hrh1-4 in mice) which initiate different downstream signaling cascades upon activation, but the specific effect of each receptor on tissue repair is poorly understood. Here, we systematically investigated the effect of selective histamine receptor agonism in laser-activated sealing and tissue repair of incisional skin wounds in immunocompetent mice. Although all four histamine receptors exhibited wound responsiveness in the epidermis, we find that activation of Hrh1, Hrh2, and Hrh4 stimulate a pro-healing immune response characterized by increased pro-resolution macrophages, reduced pro-inflammatory macrophages, and suppressed neutrophil responses. Further, activation of Hrh1 and Hrh4 stimulate angiogenesis after injury. Lastly, although Hrh1 activation resulted in enhanced epidermal epithelial-to-mesenchymal transition (EMT) in vivo and epithelialization in vitro, activation of Hrh2 suppressed both epidermal EMT and epithelialization. Activation of Hrh3, primarily found on neuronal cells, had no effect on any measure in our study. Selective histamine receptor agonism, specifically of histamine receptors Hrh-1 and 4, is a potential reparative approach to promote the efficacy of biomaterial-mediated repair of tissues, including skin.

Atherosclerotic plaques, which are characterized by endothelial oxidative stress, lipid metabolism disorders and persistent inflammation, can induce serious cardiovascular diseases. However, the pharmacotherapies currently used to treat atherosclerosis (AS), such as lipid-lowering and antithrombotic drugs, can regulate only a single pathological feature of AS, and there is still a dearth of integrated platforms for the multifaceted regulation of AS progression. Herein, we developed a synergistic combination of endogenous HS gas therapy with a multienzyme-like nanozyme (named Lip@HS) for the treatment of AS. The high affinity of the LyP-1 peptide for macrophages and foam cells within plaques allows Lip@HS to actively target atherosclerotic lesions. After cavitation was induced by low-intensity focused ultrasound (LIFU), the lipid membrane of Lip@HS was disrupted, thereby "unlocking" the enzyme-like activity of hollow mesoporous Prussian blue (HMPB) and facilitating the release of the endogenous HS donor S-allyl-L-cysteine (SAC). Notably, HS endogenously generated by enzymatic catalysis plays multiple roles, upregulating the ATP-binding cassette transporter A1 in foam cells to increase lipid efflux and promote the conversion of M1 macrophages to M2 macrophages. Moreover, the high level of reactive oxygen species in the inflammatory microenvironment of the plaque was mitigated. Overall, Lip@HS provides a specific and controlled treatment to prevent oxidative stress, inflammation and lipid metabolism disorders, making it a candidate for AS treatment.

Despite the recognized potential of inhaled nanomedicines to enhance and sustain local drug concentrations for lung cancer treatment, the influence of macrophage uptake on targeted nanoparticle delivery to and within tumors remains unclear. Here, we developed three ligand-coated nanoparticles for pulmonary delivery in lung cancer therapy: phenylboronic acid-modified nanoparticles (PBA-NPs), PBA combined with folic acid (FA-PBA-NPs), and PBA with mannose (MAN-PBA-NPs). In vitro, MAN-PBA-NPs were preferentially internalized by macrophages, whereas FA-PBA-NPs exhibited superior uptake by cancer cells compared to macrophages. Following intratracheal instillation into mice with orthotopic Lewis lung carcinoma tumors, all three nanoparticles showed similar lung retention. However, MAN-PBA-NPs were more prone to interception by lung macrophages, which limited their accumulation in tumor tissues. In contrast, both PBA-NPs and FA-PBA-NPs achieved comparable high tumor accumulation (∼11.3% of the dose). Furthermore, FA-PBA-NPs were internalized by ∼30% of cancer cells, significantly more than the 10-18% seen with PBA-NPs or MAN-PBA-NPs. Additionally, FA-PBA-NPs loaded with icaritin effectively inhibited the Wnt/β-catenin pathway, resulting in superior anti-tumor efficacy through targeted cancer cell delivery. Overall, FA-PBA-NPs demonstrated advantageous competitive uptake kinetics by cancer cells compared to macrophages, enhancing tumor targeting and therapeutic outcomes.

Delivering nanoparticles to deep tumor tissues while maintaining high therapeutic efficacy and minimizing damage to surrounding tissues has long posed a significant challenge. To address this, we have developed innovative self-propelling bowl-shaped nanomotors MSLA@GOx-PDA composed of mesoporous silica loaded with l-arginine and polydopamine, along with glucose oxidase (GOx). These nanomotors facilitate the generation of hydrogen peroxide through GOx-catalyzed glucose oxidation, thereby initiating nitric oxide production from l-arginine. This dual mechanism equips MSLA@GOx-PDA with the robust motility required for deep tumor tissue penetration while depleting essential nutrients necessary for tumor growth, consequently impeding tumor progression. In addition, near-infrared lasers have the significant advantage of being depth-penetrating and non-invasive, allowing real-time fluorescence imaging and guiding dopamine-mediated mild photothermal therapy. Notably, starvation therapy depletes intracellular adenosine triphosphate and inhibits the synthesis of heat shock proteins, thus overcoming the Achilles' heel of mild photothermal therapy and significantly enhancing the efficacy of this therapy with encouraging synergistic anti-tumour effects. Overall, the integration of biochemical and optics strategies in this nanomotor platform represents a significant advancement in deep-tissue tumor therapy. It has substantial clinical translational value and is expected to have a transformative impact on future cancer treatments.

Wound healing process has always been a focal point of concern, with a plethora of hydrogel dressings available; however, their therapeutic efficacy remains a hindrance to wound closure. This article reports on a dual-network conductive system, PEDOT:PSS-co-PSBMA/XLG (PPSX) hydrogel dressing, Constructed using poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT: PSS) in combination with zwitterionic N, N-dimethyl-N-(2-methacryloyloxyethyl)-N- (3-sulfopropyl) ammonium betaine (SBMA) and nanoclay-synthesized lithium magnesium silicate (XLG). The hydrogel powder produced from it can absorb interfacial water within 30 s via physical interactions to spontaneously form hydrogels of arbitrary shapes. With a conductivity of 1.8 s/m, it can be utilized for developing flexible sensing bioelectronic devices to monitor human activities (facial expressions, blinking, swallowing, speaking, joint movements), as well as constructing electrodes for monitoring muscle movements and motorial intensity. More importantly, PPSX hydrogel effectively inhibits bacterial growth and promotes cell proliferation, thus facilitating wound healing and presenting extensive application prospects in the medical field.

Inducing reactive oxygen species (ROS) via sonocatalysis to initiate inflammatory programmed cell death (PANoptosis) and immunogenic cell death (ICD) presents a promising strategy for activatable cancer immunotherapy. However, the limited ROS generation by sonosensitizers under ultrasound and the immunosuppressive tumor microenvironment hinder the efficiency of sono-immunotherapy. To overcome these challenges, a bismuth-based ternary heterojunction, Bi@BiO-Pt-PEG (BBOP), was developed for sonocatalytic therapy aimed at activating immune responses. This system enhances ROS production during sonocatalysis and leverages dual therapeutic mechanisms by inducing PANoptosis and ICD to achieve improved anti-tumor efficacy. BBOP forms a Z-scheme heterojunction and Schottky contact through the formation of an intermediate BiO layer and the introduction of Pt. These structures significantly enhance sonocatalytic activity, while the Pt nanozyme exhibits catalase-like behavior, supplying oxygen for sonocatalysis, boosting ROS generation, and effectively relieving tumor hypoxia to reduce immune suppression. Further in vitro and in vivo experiments confirmed BBOP's ability to activate immune responses under ultrasound, inhibiting tumor growth and metastasis. RNA sequencing revealed the therapeutic biological mechanisms. The construction of this catalytic system not only provides insights for optimizing sonosensitizers but also offers a safer and more effective sono-immunotherapy activation strategy and theoretical basis for clinical cancer treatment.

Transplantation of insulin-secreting cells provides a promising method for re-establishing the autonomous blood glucose control ability of type 1 diabetes (T1D) patients, but the low survival of the transplanted cells hinder the therapeutic efficacy. In this study, we 3D-printed an encapsulation system containing β-like cells and microvascular fragments (MVF), to create a retrivable microdevice with vascularized islets in vivo for T1D therapy. The functional β-like cells were differentiated from the urine epithelial cell-derived induced pluripotent stem cells (UiPSCs). Single-cell RNA sequencing provided an integrative study and macroscopic developmental analyses of the entire process of differentiation, which revealed the developmental trajectory of differentiation in vitro follows the developmental pattern of embryonic pancreas in vivo. The MVF were isolated from the epididymal fat pad. The microdevice with a groove structure were rapidly fabricated by the digital light processing (DLP)-3D printing technology. The β-like cells and MVF were uniformly distributed in the device. After subcutaneous transplantation into C57BL/6 mice, the microdevice have less collagen accumulation and low immune cell infiltration. Moreover, the microdevice encapsulated vascularized islets reduced hyperglycemia in 33 % of the treated mice for up to 100 days without immunosuppressants, and the humanized C-peptide was also detected in the serum of the mice. In summary, we described the microdevice-protected vascularized islets for long-term treatment of T1D, with high safety and potential clinical transformative value, and may therefore provide a translatable solution to advance the research progress of β cell replacement therapy for T1D.

Non-healing diabetic foot ulcers are the knotty public health issue due to the uncontrolled bacterial infection, prolonged inflammation, and inferior vessel remodeling. In this work, polypyrrole (Ppy) was added into the hybrid hydrogel containing polyvinyl alcohol (PVA), polyethylene glycol (PEG), and hyaluronan (HA) to acquire superior mechanism and photothermal ability. The Ppy composited hybrid hydrogel could effectively kill bacteria through accumulating heat on the hydrogel surface. RNA-Seq analysis shows that the heat accumulation could enhance phagosome of macrophage and M1 activation, which further accelerate bacteria clearance. Benefitting from the bacteria clearance, macrophage could transform its phenotype to M2 in Ppy composited hybrid hydrogel group with near infrared light (NIR) stimulation. The related genes expression in keratinization, keratinocyte differentiation, and establishment of the skin barrier in the skin were up-regulated and collagen and vascular endothelial growth factor (VEGF) expression level are also enhanced. In summary, Ppy composited hybrid hydrogel could effectively solve the issues of infection and poor wound healing in diabetic foot ulcers, making it an ideal candidate dressing for the treatment of chronic wounds.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer due to poor immunogenicity and limited immune cell infiltration, efficient therapeutics are still deficiency. Ferroptosis, a reactive oxygen species (ROS)-reliant cell death, can enhance cellular immunogenicity and then active immune system. To sustain a long-term "hot" tumour immune microenvironment (TIME), an immune-modulator is indispensable. Metformin (MET), a commonly used oral drug for type 2 diabetes, has played a vital role in fostering an immunostimulatory environment. Herein, we confirm the TIME can be remodeled by MET and further promotes ferroptosis via upregulating cellular concentration of l-Glutamine. In light of this, we have design a self-assembled MET-loaded Fe-doped polydopamine nanoparticle (Fe-PDA-MET NP) that can disorder the cellular redox homeostasis and induce robust ferroptosis under 808 nm irradiation, resulting in a strong immune response. Based on the function of MET, there is a marked increase in the infiltration of activated CD8 T cells and NK cells, which subsequently augments ferroptosis to a greater extent. Taken together, Fe-PDA-MET NPs activate a ferroptotic positive-feedback loop for effectively control TNBC progression, which offers a promising therapeutic modality to enhance the immunogenicity and reshape the TIME.