Oral Metal-Free Melanin Nanozymes for Natural and Durable Targeted Treatment of Inflammatory Bowel Disease (IBD).

Oral antioxidant nanozymes bring great promise for inflammatory bowel disease (IBD) treatment. To efficiently eliminate reactive oxygen species (ROS), various metal-based nanozymes have been developed for the treatment of IBD but their practical applications are seriously impaired by unstable ROS-eliminating properties and potential metal ion leakage in the digestive tract. Here, the authors for the first time propose metal-free melanin nanozymes (MeNPs) with excellent gastrointestinal stability and biocompatibility as a favorable therapy strategy for IBD. Moreover, MeNPs have extremely excellent natural and long-lasting characteristics of targeting IBD lesions. In view of the dominant role of ROS in IBD, the authors further reveal that oral administration of MeNPs can greatly alleviate the six major pathological features of IBD: oxidative stress, endoplasmic reticulum stress, apoptosis, inflammation, gut barrier disruption, and gut dysbiosis. Overall, this strategy highlights the great clinical application prospects of metal-free MeNPs via harnessing ROS scavenging at IBD lesions, offering a paradigm for antioxidant nanozyme in IBD or other inflammatory diseases.

WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis.

BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear. METHODS: We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes. RESULTS: Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis. CONCLUSION: Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.

Point-and-Shoot Strategy for Identification of Alcoholic Beverages.

The lack of point-and-shoot detection methods of alcoholic beverages (ABs) available for ordinary people is a common cause of the overflow of various counterfeit ABs. Here, we, for the first time, provide a point-and-shoot identification for ABs via a smartphone. Using density functional theory, we find the binding ability of an ethylenediamine-functionalized polydiacetylene (P4) can reach a desirable trade-off among organic molecules in ABs. We therefore construct a versatile array consisting of P4 with different concentrations, which is able to generate unique color response patterns toward different ABs. The color response patterns are further analyzed by a custom-designed image processing algorithm based on machine learning. Finally, the identification of ABs can be achieved by capturing and analyzing the color pattern using an imaging recognition programmer on a smartphone, and the entire process is as fast as quick response (QR) code scanning. Our point-and-shoot strategy makes the identification of ABs accessible to every mobile phone user.

Comprehensive Insights into the Multi-Antioxidative Mechanisms of Melanin Nanoparticles and Their Application To Protect Brain from Injury in Ischemic Stroke.

Nanotechnology-mediated antioxidative therapy is emerging as a novel strategy for treating a myriad of important diseases through scavenging excessive reactive oxygen and nitrogen species (RONS), a mechanism critical in disease development and progression. However, similar to antioxidative enzymes, currently studied nanoantioxidants have demonstrated scavenging activity to specific RONS, and sufficient antioxidative effects against multiple RONS generated in diseases remain elusive. Here we propose to develop bioinspired melanin nanoparticles (MeNPs) for more potent and safer antioxidative therapy. While melanin is known to function as a potential radical scavenger, its antioxidative mechanisms are far from clear, and its applications for the treatment of RONS-associated diseases have yet to be well-explored. In this study, we provide for the first time exhaustive characterization of the activities of MeNPs against multiple RONS including O2•-, H2O2, •OH, •NO, and ONOO-, the main toxic RONS generated in diseases. The potential of MeNPs for antioxidative therapy has also been evaluated in vitro and in a rat model of ischemic stroke. In addition to the broad defense against these RONS, MeNPs can also attenuate the RONS-triggered inflammatory responses through suppressing the expression of inflammatory mediators and cytokines. In vivo results further demonstrate that these unique multi-antioxidative, anti-inflammatory, and biocompatible features of MeNPs contribute to their effective protection of ischemic brains with negligible side effects.

Synergistic Tailoring of Electrostatic and Hydrophobic Interactions for Rapid and Specific Recognition of Lysophosphatidic Acid, an Early-Stage Ovarian Cancer Biomarker.

Early detection of ovarian cancer, the most lethal type of gynecologic cancer, can dramatically improve the efficacy of available treatment strategies. However, few screening tools exist for rapidly and effectively diagnosing ovarian cancer in early stages. Here, we present a facile "lock-key" strategy, based on rapid, specific detection of plasma lysophosphatidic acid (LPA, an early stage biomarker) with polydiacetylenes (PDAs)-based probe, for the early diagnosis of ovarian cancer. This strategy relies on specifically inserting LPA "key" into the PDAs "lock" through the synergistic electrostatic and hydrophobic interactions between them, leading to conformation transition of the PDA backbone with a concomitant blue-to-red color change. The detailed mechanism underlying the high selectivity of PDAs toward LPA is revealed by comprehensive theoretical calculation and experiments. Moreover, the level of LPA can be quantified in plasma samples from both mouse xenograft tumor models and patients with ovarian cancer. Impressively, this approach can be introduced into a portable point-of-care device to successfully distinguish the blood samples of patients with ovarian cancer from those of healthy people, with 100% accuracy. This work provides a valuable portable tool for early diagnosis of ovarian cancer and thus holds a great promise to dramatically improve the overall survival.

A superhydrophobic sponge with excellent absorbency and flame retardancy.

Frequent oil spillages and the industrial discharge of organic solvents have not only caused severe environmental and ecological damage, but also create a risk of fire and explosion. Therefore, it is imperative, but also challenging, to find high-performance absorbent materials that are both effective and less flammable. Here we present a superior superhydrophobic sponge that exhibits excellent absorption performance through a combination of its superhydrophobicity, high porosity, and robust stability. More importantly, it inherits the intrinsic flame-retardant nature of the raw melamine sponge, and is thus expected to reduce the risk of fire and explosion when being used as an absorbent for flammable oils and organic compounds. Moreover, the fabrication of this sponge is easy to scale up, since it does not use a complicated process or sophisticated equipment. These characteristics make the sponge a much more competitive product than the commercial absorbent, nonwoven polypropylene fabric.

Simultaneous Activation of Pyroptosis and cGAS-STING Pathway with Epigenetic/ Photodynamic Nanotheranostic for Enhanced Tumor Photoimmunotherapy.

Promoting innate immunity through pyroptosis induction or the cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway activation has emerged as a potent approach to counteract the immunosuppressive tumor microenvironment and elicit systemic antitumor immunity. However, current pyroptosis inducers and STING agonists often suffer from limitations including instability, unpredictable side effects, or inadequate intracellular expression of gasdermin and STING. Here, a tumor-specific nanotheranostic platform that combines photodynamic therapy (PDT) with epigenetic therapy to simultaneously activate pyroptosis and the cGAS-STING pathway in a light-controlled manner is constructed. This approach involves the development of oxidation-sensitive nanoparticles (NP1) loaded with the photosensitizer TBE, along with decitabine nanomicelles (NP2). NP2 enables the restoration of STING and gasdermin E (GSDME) expression, while NP1-mediated PDT facilitates the release of DNA fragments from damaged mitochondria to potentiate the cGAS-STING pathway, and promotes the activation of caspase-3 to cleave the upregulated GSDME into pore-forming GSDME-N terminal. Subsequently, the released inflammatory cytokines facilitate the maturation of antigen-presentation cells, triggering T cell-mediated antitumor immunity. Overall, this study presents an elaborate strategy for simultaneous photoactivation of pyroptosis and the cGAS-STING pathway, enabling targeted photoimmunotherapy in immunotolerant tumors. This innovative approach holds significant promise in overcoming the limitations associated with existing therapeutic modalities and represents a valuable avenue for future clinical applications.

Revitalizing Ancient Mitochondria with Nano-Strategies: Mitochondria-Remedying Nanodrugs Concentrate on Disease Control.

Mitochondria, widely known as the energy factories of eukaryotic cells, have a myriad of vital functions across diverse cellular processes. Dysfunctions within mitochondria serve as catalysts for various diseases, prompting widespread cellular demise. Mounting research on remedying damaged mitochondria indicates that mitochondria constitute a valuable target for therapeutic intervention against diseases. But the less clinical practice and lower recovery rate imply the limitation of traditional drugs, which need a further breakthrough. Nanotechnology has approached favorable regiospecific biodistribution and high efficacy by capitalizing on excellent nanomaterials and targeting drug delivery. Mitochondria-remedying nanodrugs have achieved ideal therapeutic effects. This review elucidates the significance of mitochondria in various cells and organs, while also compiling mortality data for related diseases. Correspondingly, nanodrug-mediate therapeutic strategies and applicable mitochondria-remedying nanodrugs in disease are detailed, with a full understanding of the roles of mitochondria dysfunction and the advantages of nanodrugs. In addition, the future challenges and directions are widely discussed. In conclusion, this review provides comprehensive insights into the design and development of mitochondria-remedying nanodrugs, aiming to help scientists who desire to extend their research fields and engage in this interdisciplinary subject.

Nanoparticulate X-ray computed tomography contrast agents: from design validation to in vivo applications.

X-ray computed tomography (CT) is one of the most powerful noninvasive diagnostic imaging techniques in modern medicine. Nevertheless, the iodinated molecules used as CT contrast agents in the clinic have relatively short circulation times in vivo, which significantly restrict the applications of this technique in target-specific imaging and angiography. In addition, the use of these agents can present adverse. For example, an adult patient typically receives approximately 70 mL of iodinated agent (350 mg I/mL) because of iodine's low contrast efficacy. Rapid renal clearance of such a large dose of these agents may lead to serious adverse effects. Furthermore, some patients are hypersensitive to iodine. Therefore, biomedical researchers have invested tremendous efforts to address these issues. Over the past decade, advances in nanoscience have created new paradigms for imaging. The unique properties of nanomaterials, such as their prolonged circulating half-life, passive accumulation at the tumor sites, facile surface modification, and integration of multiple diverse functions into a single particle, make them advantageous for in vivo applications. However, research on the utilization of nanomaterials for CT imaging has lagged far behind their applications for other imaging techniques such as MRI and fluorescence imaging because of the challenges in the preparation of cost-effective nanoparticulate CT contrast agents with excellent biocompatibility, high contrast efficacy, long in vivo circulation time, and long-term colloidal stability in physiological environments. This Account reviews our recent work on the design and in vivo applications of nanoparticulate CT contrast agents. By optimizing the contrast elements in the nanoparticles according to the fundamental principles of X-ray imaging and by employing the surface engineering approaches that we and others have developed, we have synthesized several nanoparticulate CT contrast agents with excellent imaging performance. For example, a novel Yb-based nanoparticulate agent provides enhanced contrast efficacy compared to currently available CT contrast agents under normal operating conditions. To deal with special situations, we integrated both Ba and Yb with great differential in K-edge value into a single particle to yield the first example of binary contrast agents. This agent displays much higher contrast than iodinated agents at different voltages and is highly suited to diagnostic imaging of various patients. Because of their prolonged in vivo circulation time and extremely low toxicity, these agents can be used for angiography.

Corrigendum: 2D-nanomaterials for AKI treatment.

[This corrects the article DOI: 10.3389/fbioe.2023.1159989.].

2D-nanomaterials for AKI treatment.

Acute kidney injury has always been considered a sword of Damocles over hospitalized patients and has received increasing attention due to its high morbidity, elevated mortality, and poor prognosis. Hence, AKI has a serious detrimental impact not only on the patients, but also on the whole society and the associated health insurance systems. Redox imbalance caused by bursts of reactive oxygen species at the renal tubules is the key cause of the structural and functional impairment of the kidney during AKI. Unfortunately, the failure of conventional antioxidant drugs complicates the clinical management of AKI, which is limited to mild supportive therapies. Nanotechnology-mediated antioxidant therapies represent a promising strategy for AKI management. In recent years, two-dimensional (2D) nanomaterials, a new subtype of nanomaterials with ultrathin layer structure, have shown significant advantages in AKI therapy owing to their ultrathin structure, large specific surface area, and unique kidney targeting. Herein, we review recent progress in the development of various 2D nanomaterials for AKI therapy, including DNA origami, germanene, and MXene; moreover, we discuss current opportunities and future challenges in the field, aiming to provide new insights and theoretical support for the development of novel 2D nanomaterials for AKI treatment.

Antioxidative 0-dimensional nanodrugs overcome obstacles in AKI antioxidant therapy.

Acute kidney injury (AKI) is a commonly encountered syndrome associated with various aetiologies and pathophysiological processes leading to enormous health risks and economic losses. In the absence of specific drugs to treat AKI, hemodialysis remains the primary clinical treatment for AKI patients. The revelation of the pathology opens new horizons for antioxidant therapy in the treatment of AKI. However, small molecule antioxidant drugs and common nanozymes have failed to challenge AKI due to their unsatisfactory drug properties and renal physiological barriers. 0-Dimensional (0D) antioxidant nanodrugs stand out at this time thanks to their small size and high performance. Recently, a number of research studies have been carried out around 0D nanodrugs for alleviating AKI, and their multi-antioxidant enzyme mimetic activities, smooth glomerular filtration barrier permeability and excellent biocompatibility have been investigated. Here, we comprehensively summarize recent advances in 0D nanodrugs for AKI antioxidant therapy. We classify these representative studies into three categories according to the characteristics of 0D nanomaterials, namely ultra-small metal nanodots, inorganic non-metallic quantum dots and polymer nanodots. We focus on the antioxidant mechanisms and their distribution in vivo in each inspiring work, and the purpose and ingenuity of each design are rigorously captured and described. Finally, we provide our reflections and prospects for 0D antioxidant nanodrugs in AKI treatment. This mini review provides unique insights and valuable clues in the design of 0D nanodrugs and other kidney absorbable drugs.

Surface control approach for growth of cerium oxide on flower-like molybdenum disulfide nanosheets enables superior removal of uremic toxins.

Due to the high incidence of kidney disease, there is an urgent need to develop wearable artificial kidneys. This need is further exacerbated by the coronavirus disease 2019 pandemic. However, the dialysate regeneration system of the wearable artificial kidney has a low adsorption capacity for urea, which severely limits its application. Therefore, nanomaterials that can effectively remove uremic toxins, especially urea, to regenerate dialysate are required and should be further investigated and developed. Herein, flower-like molybdenum disulphide (MoS2) nanosheets decorated with highly dispersed cerium oxide (CeO2) were prepared (MoS2/CeO2), and their adsorption performances for urea, creatinine, and uric acid were studied in detail. Due to the open interlayer structures and the combination of MoS2 and CeO2, which can provide abundant adsorption active sites, the MoS2/CeO2 nanomaterials present excellent uremic toxin adsorption activities. Further, uremic toxin adsorption capacities were also assessed using a self-made fixed bed device under dynamic conditions, with the aim of developing MoS2/CeO2 for the practical adsorption of uremic toxins. In addition, the biocompatibility of MoS2/CeO2 was systematically analyzed using hemocompatibility and cytotoxicity assays. Our data suggest that MoS2/CeO2 can be safely used for applications requiring close contact with blood. Our findings confirm that novel 2-dimensional nanomaterial adsorbents have significant potential for dialysis fluid regeneration.

The Notch signaling-regulated angiogenesis in rheumatoid arthritis: pathogenic mechanisms and therapeutic potentials.

Angiogenesis plays a key role in the pathological process of inflammation and invasion of the synovium, and primarily drives the progression of rheumatoid arthritis (RA). Recent studies have demonstrated that the Notch signaling may represent a new therapeutic target of RA. Although the Notch signaling has been implicated in the M1 polarization of macrophages and the differentiation of lymphocytes, little is known about its role in angiogenesis in RA. In this review, we discourse the unique roles of stromal cells and adipokines in the angiogenic progression of RA, and investigate how epigenetic regulation of the Notch signaling influences angiogenesis in RA. We also discuss the interaction of the Notch-HIF signaling in RA's angiogenesis and the potential strategies targeting the Notch signaling to improve the treatment outcomes of RA. Taken together, we further suggest new insights into future research regarding the challenges in the therapeutic strategies of RA.

Emerging Sonodynamic Therapy-Based Nanomedicines for Cancer Immunotherapy.

Cancer immunotherapy effect can be greatly enhanced by other methods to induce immunogenic cell death (ICD), which has profoundly affected immunotherapy as a highly efficient paradigm. However, these treatments have significant limitations, either by causing damage of the immune system or limited to superficial tumors. Sonodynamic therapy (SDT) can induce ICD to promote immunotherapy without affecting the immune system because of its excellent spatiotemporal selectivity and low side effects. Nevertheless, SDT is still limited by low reactive oxygen species yield and the complex tumor microenvironment. Recently, some emerging SDT-based nanomedicines have made numerous attractive and encouraging achievements in the field of cancer immunotherapy due to high immunotherapeutic efficiency. However, this cross-cutting field of research is still far from being widely explored due to huge professional barriers. Herein, the characteristics of the tumor immune microenvironment and the mechanisms of ICD are firstly systematically summarized. Subsequently, the therapeutic mechanism of SDT is fully summarized, and the advantages and limitations of SDT are discussed. The representative advances of SDT-based nanomedicines for cancer immunotherapy are further highlighted. Finally, the application prospects and challenges of SDT-based immunotherapy in future clinical translation are discussed.

Nanodrugs alleviate acute kidney injury: Manipulate RONS at kidney.

Currently, there are no clinical drugs available to treat acute kidney injury (AKI). Given the high prevalence and high mortality rate of AKI, the development of drugs to effectively treat AKI is a huge unmet medical need and a research hotspot. Although existing evidence fully demonstrates that reactive oxygen and nitrogen species (RONS) burst at the AKI site is a major contributor to AKI progression, the heterogeneity, complexity, and unique physiological structure of the kidney make most antioxidant and anti-inflammatory small molecule drugs ineffective because of the lack of kidney targeting and side effects. Recently, nanodrugs with intrinsic kidney targeting through the control of size, shape, and surface properties have opened exciting prospects for the treatment of AKI. Many antioxidant nanodrugs have emerged to address the limitations of current AKI treatments. In this review, we systematically summarized for the first time about the emerging nanodrugs that exploit the pathological and physiological features of the kidney to overcome the limitations of traditional small-molecule drugs to achieve high AKI efficacy. First, we analyzed the pathological structural characteristics of AKI and the main pathological mechanism of AKI: hypoxia, harmful substance accumulation-induced RONS burst at the renal site despite the multifactorial initiation and heterogeneity of AKI. Subsequently, we introduced the strategies used to improve renal targeting and reviewed advances of nanodrugs for AKI: nano-RONS-sacrificial agents, antioxidant nanozymes, and nanocarriers for antioxidants and anti-inflammatory drugs. These nanodrugs have demonstrated excellent therapeutic effects, such as greatly reducing oxidative stress damage, restoring renal function, and low side effects. Finally, we discussed the challenges and future directions for translating nanodrugs into clinical AKI treatment.

Passively-targeted mitochondrial tungsten-based nanodots for efficient acute kidney injury treatment.

Acute kidney injury (AKI) can lead to loss of kidney function and a substantial increase in mortality. The burst of reactive oxygen species (ROS) plays a key role in the pathological progression of AKI. Mitochondrial-targeted antioxidant therapy is very promising because mitochondria are the main source of ROS in AKI. Antioxidant nanodrugs with actively targeted mitochondria have achieved encouraging success in many oxidative stress-induced diseases. However, most strategies to actively target mitochondria make the size of nanodrugs too large to pass through the glomerular system to reach the renal tubules, the main damage site of AKI. Here, an ultra-small Tungsten-based nanodots (TWNDs) with strong ROS scavenging can be very effective for treatment of AKI. TWNDs can reach the tubular site after crossing the glomerular barrier, and enter the mitochondria of the renal tubule without resorting to complex active targeting strategies. To our knowledge, this is the first time that ultra-small negatively charged nanodots can be used to passively target mitochondrial therapy for AKI. Through in-depth study of the therapeutic mechanism, such passive mitochondria-targeted TWNDs are highly effective in protecting mitochondria by reducing mitochondrial ROS and increasing mitophagy. In addition, TWNDs can also reduce the infiltration of inflammatory cells. This work provides a new way to passively target mitochondria for AKI, and give inspiration for the treatment of many major diseases closely related to mitochondria, such as myocardial infarction and cerebral infarction.

Natural Targeting Potent ROS-Eliminating Tungsten-Based Polyoxometalate Nanodots for Efficient Treatment of Pulmonary Hypertension.

Pulmonary hypertension (PH) is a disease of pulmonary artery stenosis and blockage caused by abnormal pulmonary artery smooth muscle cells (PASMCs), with high morbidity and mortality. High levels of reactive oxygen species (ROS) in pulmonary arteries play a crucial role in inducing phenotypic switch and abnormal proliferation of PASMCs. However, antioxidants are rarely approved for the treatment of PH because of a lack of targeting and low bioavailability. In this study, the presence of an enhanced permeability and retention effect (EPR)-like effect in the pulmonary arteries of PH is revealed by tissue transmission electron microscopy (TEM). Subsequently, for the first time, tungsten-based polyoxometalate nanodots (WNDs) are developed with potent elimination of multiple ROS for efficient treatment of PH thanks to the high proportion of reduced W5+ . WNDs are effectively enriched in the pulmonary artery by intravenous injection because of the EPR-like effect of PH, and significantly prevent the abnormal proliferation of PASMCs, greatly improve the remodeling of pulmonary arteries, and ultimately improve right heart function. In conclusion, this work provides a novel and effective solution to the dilemma of targeting ROS for the treatment of PH.

Precisely Inhibiting Excessive Intestinal Epithelial Cell Apoptosis to Efficiently Treat Inflammatory Bowel Disease with Oral Pifithrin-α Embedded Nanomedicine (OPEN).

The increased incidence of inflammatory bowel disease (IBD) has seriously affected the life quality of patients. IBD develops due to excessive intestinal epithelial cell (IEC) apoptosis, disrupting the gut barrier, colonizing harmful bacteria, and initiating persistent inflammation. The current therapeutic approaches that reduce inflammation are limited. Although IBD can be treated significantly by directly preventing IEC apoptosis, achieving this therapeutic approach remains challenging. Accordingly, the authors are the first to develop an oral pifithrin-α (PFTα, a highly specific p53 inhibitor) embedded nanomedicine (OPEN) to effectively treat IBD by inhibiting excessive IEC apoptosis. As a major hub for various stressors, p53 is a central determinant of cell fate, and its inhibition can effectively reduce excessive IEC apoptosis. The tailored OPEN can precisely inhibit the off-target and inactivation resulting from PFTα entry into the bloodstream. Subsequently, it persistently targets IBD lesions with high specificity to inhibit the pathological events caused by excessive IEC apoptosis. Eventually, OPEN exerts a significant curative effect compared with the clinical first-line drugs 5-aminosalicylic acid (5-ASA) and dexamethasone (DEX). Consequently, the OPEN therapeutic strategy provides new insights into comprehensive IBD therapy.

Apoptotic Neutrophil Membrane-Camouflaged Liposomes for Dually Targeting Synovial Macrophages and Fibroblasts to Attenuate Osteoarthritis.

No current pharmacological approach is capable of simultaneously inhibiting the symptomatology and structural progression of osteoarthritis. M1 macrophages and activated synovial fibroblasts (SFs) mutually contribute to the propagation of joint pain and cartilage destruction in osteoarthritis. Here, we report the engineering of an apoptotic neutrophil membrane-camouflaged liposome (termed "NM@Lip") for precise delivery of triamcinolone acetonide (TA) by dually targeting M1 macrophages and activated SFs in osteoarthritic joints. NM@Lip has a high cellular uptake in M1 macrophages and activated SFs. Furthermore, TA-loaded NM@Lip (TA-NM@Lip) effectively repolarizes M1 macrophages to the M2 phenotype and transforms pathological SFs to the deactivated phenotype by inhibiting the PI3K/Akt pathway. NM@Lip retains in the joint for up to 28 days and selectively distributes into M1 macrophages and activated SFs in synovium with low distribution in cartilage. TA-NM@Lip decreases the levels of pro-inflammatory cytokines, chemokines, and cartilage-degrading enzymes in osteoarthritic joints. In a rodent model of osteoarthritis-related pain, a single intra-articular TA-NM@Lip injection attenuates synovitis effectively and achieves complete pain relief with long-lasting effects. In a rodent model of osteoarthritis-related joint degeneration, repeated intra-articular TA-NM@Lip injections induce no obvious cartilage damage and effectively attenuate cartilage degeneration. Taken together, TA-NM@Lip represents a promising nanotherapeutic approach for osteoarthritis therapy.