INFLAMMATION RESEARCH
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2025
·Vol. 74
·期 1
·1-14
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IF 5.4
Zhang Yan,Yan Xin,Fu Xiao-lei,Yang Hai-bing,Yan Yi-min,He He-fan,Yang Li
Background Clinical studies have demonstrated that multiple inflammatory related proteins are associated with hypertrophic cardiomyopathy (HCM). However, the precise role of these factors in the pathogenesis of HCM remains uncertain. Methods The link between inflammatory related proteins and HCM was analyzed using Mendelian randomization (MR), followed by bioinformatics to explore the role of inflammatory related proteins in HCM. In vivo and in vitro models of HCM were established to elucidate how inflammatory related proteins influence HCM progression. Results Our MR analysis revealed a negative correlation between the inflammation related protein CX3CL1 and HCM. Bioinformatics and in vivo data similarly demonstrated a reduction in CX3CL1 expression in HCM. CX3CL1 was found to be mainly expressed in cardiomyocytes and endothelial cells via the Human Protein Atlas database and its’ expression in both cells was obviously downregulated after being treated by angiotensin-II. Importantly, functional characteristics and correlation analysis of CX3CL1 indicated that it was most closely associated with macrophages efferocytosis. Consequently, we examined the signature molecules (AXL, MERTK, and TYRO3) associated with efferocytosis, which revealed a significant decrease in their expression in HCM. Notably, recombinant mouse CX3CL1 (rm-CX3CL1) reversed this process. Conclusions In conclusion, CX3CL1-meidated impaired efferocytosis plays a critical role in the initiation and development of HCM, and modulation of CX3CL1 may prove advantageous in managing HCM progression.
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Research
·
2025
·
IF 10.7
Linfeng Li,Jing Zhang,Caiping Yan,Yongjie Wen,Lifu Jia,Xiyang Tang,Yuan Yong,Ke Jiang,Hanfeng Yang,Lu Chen,Yuling Li
Efferocytosis, mediated by macrophages and dendritic cells (DCs), clears apoptotic cells to maintain tissue homeostasis, suppress inflammation, and promote repair. In diabetic wounds, hyperglycemia disrupts their efferocytic function, impeding healing progression. Therefore, restoring the efferocytic capacity of DCs and macrophages and establishing a dynamic “cyclic efferocytosis” between these 2 cell types are critical for diabetic wound regeneration. DCs are key drivers of cyclic efferocytosis because of their tissue-resident properties and glycogenolysis-driven energy supply. We postulated that targeted modulation of DCs was a promising strategy to establish this cycle. We developed GPP-M@L hydrogel, coencapsulating metformin (Met) and DC-targeted MnPOM nanozyme liposomes (Lipo-Dcpep@MnPOM). Met improved the high-glucose microenvironment. Lipo-Dcpep@MnPOM restored DC efferocytosis by enhancing mitochondrial adenosine triphosphate production. Treated DCs activated macrophage phosphatidylinositol 3-kinase/Akt signaling via paracrine effects, reinstating macrophage efferocytosis and promoting M2 polarization. Macrophages reciprocally enhanced DC efferocytosis via Rap1 and mitochondrial oxidative phosphorylation (OXPHOS), establishing a self-sustaining “cyclic efferocytosis” loop. This process further promoted regeneration by regulating endothelial cells and fibroblasts. Efficacy was confirmed in vitro and in diabetic rat models. In conclusion, by establishing a dynamic cyclic efferocytosis process using GPP-M@L, this study, grounded in the regulatory framework of “hyperglycemia-impaired immune homeostasis–efferocytosis cycle”, provides a novel therapeutic paradigm for healing diabetic wounds and other immune homeostasis-related diseases.
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Reproductive Biology and Endocrinology
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2025
·Vol. 23
·期 1
·1-15
·
IF 4.7
Sun Lu,Huang Jiayu,Wang Xuezi,Huang Peng,Dong Baolin,Liang Zehang,Wu Jiahong,Wang Jiancheng
Background Testosterone deficiency (TD) occurs most frequently in older men and can cause many health problems. Testosterone replacement therapy (TRT) is widely used to treat TD, but this regimen can lead to a series of side effects. Stem cell therapy has been wildly studied in vitro. However, due to the multidirectional differentiation potential and heterogeneity of stem cells, it is difficult to achieve the good efficiency and reproducibility in basic research and clinical applications. This study aims to identify a new strategy for the treatment of TD. Methods Bone marrow-derived mesenchymal stromal cells (BMSCs) were enucleated by Ficoll density gradient centrifugation. The organelles and cellular functions of enucleated BMSCs were analyzed by immunofluorescence staining and flow cytometry. Extracellular vesicles (EVs) were isolated by ultracentrifugation and characterized. For the animal studies, enucleated BMSCs were labelled with Mitotracker and injected into ethane dimethanesulfone (EDS)-treated rats. Testosterone production and spermatogenesis were detected at different time points through various tests. To determine the mechanism of efferocytosis, we analysed the number of macrophages by immunofluorescence staining and quantitative real-time polymerase chain reaction (qRT-PCR). Results The injection of enucleated BMSCs (Cargocytes) into the testes of EDS-treated rats restored the levels of serum testosterone, increased the number of Leydig cells (LCs), and improved spermatogenesis. We found that enucleated BMSCs underwent apoptosis earlier than BMSCs did. Subsequently, testicular interstitial macrophages phagocytosed apoptotic enucleated BMSCs through efferocytosis. Efferocytosis promoted macrophage polarization from the M1 to the M2 phenotype, reduced the expression of proinflammatory cytokines, and decreased the levels of inflammation and oxidative stress. Conclusions In summary, this study pioneered the application of stromal cell enucleation technology to repair tissue damage in the reproductive system, explored the potential of cell burial in the treatment of reproductive system diseases and provided a new approach for the clinical treatment of male infertility.
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Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Yizhou Wu,Hongyan Zhou,Hao Liu,Jiayao Hu,Yue Sun,Wei Yan,Chunyi Tong,Ying Kong,Bin Liu
Advanced atherosclerosis is the major global cause of death, as featured by the aggregation of apoptotic cells (ACs) in necrotic cores. The defective efferocytosis and dysfunctional cholesterol efflux of macrophages are the main reasons for forming necrotic cores in advanced atherosclerosis. In this study, we constructed self-assembled procyanidins (PC) NPs for loading pitavastatin (Pita). The designed HA@PC@Pita NPs with hyaluronic acid (HA) modification combined the advantages of efferocytosis restoration of Pita and cholesterol efflux enhancement of PC. In vitro assay indicated that HA@PC@Pita NPs could induce M1/M2 repolarization and upregulate ERK5/Mertk expression to restore efferocytosis of macrophages. Simultaneously, HA@PC@Pita NPs notably promoted cholesterol efflux by promoting macrophage lipophagy, a selective autophagy of lipid droplets. In vivo study showed that HA@PC@Pita NPs cleared necrotic core and enhanced plaque stability in the ApoE −/− mice model with advanced atherosclerosis. Taken together, this study demonstrated the potential of HA@PC@Pita NPs for the treatment of advanced atherosclerosis.
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Advanced Science
·
2024
·Vol. 11
·期 29
·2308325
·
IF 14.3
Run Han,Zhengyu Ren,Qi Wang,Haidong Zha,Erjin Wang,Mingyue Wu,Ying Zheng,Jia-Hong Lu
Macrophages play pivotal roles in the regulation of inflammatory responses and tissue repair, making them a prime target for inflammation alleviation. However, the accurate and efficient macrophages targeting is still a challenging task. Motivated by the efficient and specific removal of apoptotic cells by macrophages efferocytosis, a novel biomimetic liposomal system called Effero-RLP (Efferocytosis-mediated Red blood cell hybrid Liposomes) is developed which incorporates the membrane of apoptotic red blood cells (RBCs) with liposomes for the purpose of highly efficient macrophages targeting. Rosiglitazone (ROSI), a PPARγ agonist known to attenuate macrophage inflammatory responses, is encapsulated into Effero-RLP as model drug to regulate macrophage functions in DSS-induced colitis mouse model. Intriguingly, the Effero-RLP exhibits selective and efficient uptake by macrophages, which is significantly inhibited by the efferocytosis blocker Annexin V. In animal models, the Effero-RLP demonstrates rapid recognition by macrophages, leading to enhanced accumulation at inflammatory sites. Furthermore, ROSI-loaded Effero-RLP effectively alleviates inflammation and protects colon tissue from injury in the colitis mouse model, which is abolished by deletion of macrophages from mice model. In conclusion, the study highlights the potential of macrophage targeting using efferocytosis biomimetic liposomes. The development of Effero-RLP presents novel and promising strategies for alleviating inflammation.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Quan Liao,Shichao Zhang,Yuhan Xie,Qidan Tan,Tengfei Li,Shushuai Yang,Chenglong Xu,Zhouting Tuo,Rui Yao,Longchao Zhang,Haiwen Zhou,Yuanjiong Qi,Shiyong Qi
Background Acute kidney injury (AKI) remains a major clinical challenge and is largely driven by excessive oxidative stress, inflammatory responses, and tubular cell apoptosis. However, effective therapeutic strategies that simultaneously target these pathological processes are still lacking. Results We developed a pH-responsive ultrasmall Fe–kaempferol (Fe–Kae) nanoplatform with coordinated antioxidant and anti-inflammatory activities for AKI treatment. Owing to their ultrasmall size and pH-responsive properties, Fe–Kae nanoparticles preferentially accumulated in injured renal tissues and exhibited robust renoprotective effects in multiple murine AKI models, including ischemia–reperfusion injury, cisplatin-induced nephrotoxicity, and calcium oxalate–induced kidney injury. Integrated transcriptomic and metabolomic analyses of ischemia–reperfusion–injured kidneys revealed that Fe–Kae treatment markedly enhanced efferocytosis-associated pathways and induced coordinated metabolic reprogramming, characterized by optimized tricarboxylic acid cycle activity and enhanced glutathione metabolism. Conclusions This study establishes a nanomedicine-based therapeutic strategy that couples efferocytosis enhancement with metabolic reprogramming to achieve effective renoprotection. Our findings highlight pH-responsive ultrasmall metal–polyphenol nanoplatforms as a promising paradigm for the treatment of AKI. Graphical Open in a new tab Graphical Supplementary Information The online version contains supplementary material available at 10.1186/s12951-026-04534-8.
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ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Cui Tang,Hui Wang,Lina Guo,Chan Zou,Jianming Hu,Hanyong Zhang,Wenhu Zhou,Guoping Yang
Atherosclerosis (AS) is a major contributor to cardiovascular diseases, necessitating the development of novel therapeutic strategies to alleviate plaque burden. Macrophage efferocytosis, the process by which macrophages clear apoptotic and foam cells, plays a crucial role in plaque regression. However, this process is impaired in AS lesions due to the overexpression of CD47, which produces a “do not eat me” signal. In this study, we investigated the potential of CpG, a toll-like receptor 9 agonist, to enhance macrophage efferocytosis for AS therapy. We demonstrated that CpG treatment promoted the engulfment of CD47-positive apoptotic cells and foam cells by macrophages. Mechanistically, CpG induced a metabolic shift in macrophages characterized by enhanced fatty acid oxidation and de novo lipid biosynthesis, contributing to its pro-efferocytic effect. To enable in vivo application, we conjugated CpG on silver nanoparticles (AgNPs) to form CpG-AgNPs, which could protect CpG from biological degradation, promote its cellular uptake, and release CpG in response to intracellular glutathione. Combining the intrinsic antioxidative and anti-inflammatory abilities of AgNPs, such nanomedicine displayed multifunctionalities to simultaneously promote macrophage efferocytosis and repolarization. In an ApoE–/– mouse model, intravenous administration of CpG-AgNPs effectively targeted atherosclerotic plaques and exhibited potent therapeutic efficacy with excellent biocompatibility. Our study provides valuable insights into CpG-induced macrophage efferocytosis and highlights the potential of CpG-AgNPs as a promising therapeutic strategy for AS.
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Research
·
2026
·
IF 12.9
Ruidi Xia,Junlong Xue,Xinyu Liu,Mixiao Gui,Linjun Zhang,Yihua Cai,Zhengjie Shan,Guanqi Liu,Xuran Liao,Zhuofan Chen,Jieyun Xu,Zetao Chen
Decellularized extracellular matrix (dECM) leverages native architecture and bioactive components for tissue regeneration, yet its therapeutic efficacy is constrained by donor tissue maturity. While mature-tissue-derived dECM (Mat-dECM) lacks developmental signals, developmental-stage dECM (Dev-dECM) retains these cues but is limited by scarce sources and poor adaptability to adult environments. Here, we proposed postnatal maxillofacial odontogenic tissues as a novel Dev-dECM (pDev-dECM) source. Leveraging its unique trans-stage development—spanning embryonic crown formation to postnatal periodontal maturation—pDev-dECM balances developmental potency with adult environment adaptability. Multiomics comparative analysis revealed that pDev-dECM is enriched in arginylglycylaspartic-acid-containing proteins, which activate macrophage integrin αvβ5-mediated efferocytosis. This mechanism drives macrophage polarization toward regenerative M2 phenotypes, ensures adaptability to the adult environment, and reprograms mesenchymal stem cells to orchestrate developmental recapitulation. Consequently, pDev-dECM not only enabled in situ hierarchical regeneration of the periodontal complex but also facilitated cross-organ hierarchical regeneration in skin and muscle defect models. These findings demonstrate that pDev-dECM exerts spatiotemporal control over developmental recapitulation, establishing a universal biomaterial paradigm for multiscale tissue reconfiguration.
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Boya Zhang,Hanze Du,Lei Huang,Lijun Liu,Jing Cui,Linlin Wen,Junguang Liu,Wenhao Zhai,Rongrong Ye,Yuhuan Li,Kexuan Liu,Wangni Xie,Xue Zhang,Xinchen Liu,Huan Wang,Ying Xue,Shi Chen,Hui Pan,Daowei Li,Hongchen Sun
Osteoporosis, a prevalent age-related condition, is associated with chronic inflammation and impaired bone repair, exacerbated by defective efferocytosis—the clearance of apoptotic cells (ACs) by macrophages. Therefore, enhancing the efferocytosis by apoptotic cell injection to reduce inflammation is a potential strategy for the treatment of osteoporosis. However, phagocytes experience metabolic stress such as endoplasmic reticulum (ER) stress during continuous ACs uptake, reflecting requirement for safe and effective solutions. To address this, we develop a novel therapy utilizing liquid nitrogen-frozen cells loaded with docosahexaenoic acid (DHA, FrozCell-DHA). In an ovariectomy (OVX)-induced mouse model of postmenopausal osteoporosis, FrozCell-DHA significantly enhance macrophage efferocytosis, alleviate inflammation, and reduce bone loss. Mechanistically, DHA reduces ER stress by activating the PPARγ pathway, driving continuous efferocytosis. These findings highlight FrozCell-DHA as a safe therapeutic approach, capable of restoring efferocytosis and promoting bone regeneration. Our study indicates the potential of FrozCell-DHA as a transformative therapy for osteoporosis, providing a promising proposal for bone repair and healthy aging.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-26
·
IF 12.6
Mu Zhenlong,Chen Yang,Hu Yunfeng,Wang Hui,Li Jin
Neuroinflammation, characterized by microglial overactivation and oxidative stress, plays a critical role in the initiation and progression of Alzheimer’s disease (AD). In this study, we focus on simulating the natural efferocytosis process to reprogram microglial and mitigate chronic neuroinflammation for combinational AD therapy. To achieve this goal, engineered apoptotic bodies derived from brain metastatic tumor cells (LAbs) are successfully developed. Specifically, LAbs-based nanocomposites were fabricated by hybridizing LAbs with liposomes co‐loaded with manganese dioxide nanoenzyme (BMn) and autophagy‐activating rapamycin (Rapa), referred to as LAbs@Lip@BMn/Rapa. LAbs@Lip@BMn/Rapa exhibits efficient BBB penetration via LAbs‐associated brain metastasis propensity of apoptotic bodies. Within the AD microenvironment, oxygen produced through BMn catalyzation in response to H 2 O 2 triggers the structural disintegration of LAbs‐camouflaged liposomes and their reassembly into ultra‐small vesicles, thereby significantly enhancing intracranial delivery efficiency. In vitro and in vivo experiments confirm that this multi‐target strategy effectively normalizes microglia toward anti-inflammatory M2 phenotype, scavenges reactive oxide species (ROS) accumulation, promotes β‐amyloid and phosphorylated tau clearance through synergistic intervention, restores the pathological microenvironment in the brain, and enhances cognitive functions in AD model mice. This study demonstrates a novel LAbs‐based biomimetic construction strategy that effectively penetrates the BBB and regulates microglia functions, offering a promising approach for AD treatment. Graphical abstract
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ACS Nano
·
2024
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IF 15.8
Zhengxi Wang,Xudong Zhang,Quan Liu,Xianli Hu,Jiawei Mei,Jun Zhou,Xianzuo Zhang,Dongdong Xu,Wanbo Zhu,Zheng Su,Chen Zhu
There is an increasingly growing demand to balance tissue repair guidance and opportunistic infection (OI) inhibition in clinical implant surgery. Herein, we developed a nanoadjuvant for all-stage tissue repair guidance and biofilm-responsive OI eradication via in situ incorporating Cobaltiprotoporphyrin (CoPP) into Prussian blue (PB) to prepare PB-CoPP nanozymes (PCZs). Released CoPP possesses a pro-efferocytosis effect for eliminating apoptotic and progressing necrotic cells in tissue trauma, thus preventing secondary inflammation. Once OIs occur, PCZs with switchable nanocatalytic capacity can achieve bidirectional pyroptosis regulation. Once reaching the acidic biofilm microenvironment, PCZs possess peroxidase (POD)-like activity that can generate reactive oxygen species (ROS) to eradicate bacterial biofilms, especially when synergized with the photothermal effect. Furthermore, generated ROS can promote macrophage pyroptosis to secrete inflammatory cytokines and antimicrobial proteins for biofilm eradication in vivo. After eradicating the biofilm, PCZs possess catalase (CAT)-like activity in a neutral environment, which can scavenge ROS and inhibit macrophage pyroptosis, thereby improving the inflammatory microenvironment. Briefly, PCZs as nanoadjuvants feature the capability of all-stage tissue repair guidance and biofilm-responsive OI inhibition that can be routinely performed in all implant surgeries, providing a wide range of application prospects and commercial translational value.
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CHEMICAL ENGINEERING JOURNAL
·
2026
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IF 12.5
Shengming Wu,Huawei Liu,Han Zhou,Jingwen Qin,Chenlong He,Ming Yin,Hongyi Zhang,Shan Hua,Zhonghua Liu,Yilong Wang
Dual-protein co-delivery nanocarriers enabling full-course ICD through to antigen presentation • A tumor-targeted nanoplatform (P/A@MnO₂-M) was developed to achieve full-course ICD activation, from tumor-specific ICD induction via PPE to efferocytosis blockade via Annexin A5. This strategy bridges cell death induction, DAMPs release, and antigen presentation, addressing the challenge of transient signals and insufficient presentation in conventional ICD approaches. • Distinct regulation of different phagocytic cell types to block clearance while preserving antigen presentation • This study precisely regulates different phagocytic cell types by selectively blocking PS-dependent immunosilent efferocytosis in macrophages while preserving dendritic cell-mediated uptake through CRT pathways, ensuring efficient antigen presentation and subsequent immune activation. • Enhancement of macrophage antigen-presenting function to bridge ICD to adaptive immunity • Beyond conventional ICD strategies, this platform enhances the antigen-presenting capacity of macrophages, enabling effective antigen delivery to dendritic cells and T cells, bridging innate sensing with adaptive immune activation, and addressing the overlooked role of macrophages in ICD-based immunity. • Integration with immune checkpoint blockade to overcome immune inertia in cold tumors • By prolonging DAMPs exposure and remodeling the tumor microenvironment, P/A@MnO₂-M enhances responsiveness to αPD-L1 therapy, effectively overcoming immune inertia in cold tumors and demonstrating strong potential for synergistic immunotherapy. Immunogenic cell death (ICD) holds great promise for eliciting antitumor immunity but remains challenged by rapid signal clearance, insufficient antigen presentation, and dominant immunosuppression within the tumor microenvironment. Here, we report a sequential immune activation strategy through precise killing and phagocytosis regulation based on a porous MnO 2 -based nanoplatform (P/A@MnO 2 -M) integrating tumor-specific ICD induction with efferocytosis blockade for addressing transient ICD signals and immune tolerance. This nanotherapeutics prolongs danger signal exposure, prolonged immunogenic signaling, and strengthens immune activation upon a tumor membraned encapsulated carrier with co-delivery of PPE, a histone H1-targeting protease, and Annexin A5 (ANXA5), a PS-binding protein. Notably, it reprograms macrophages toward enhanced antigen presentation, facilitates dendritic cell activation and CD8 + T cell infiltration, completing the full ICD process from induction to adaptive immunity. In-vivo studies also confirm the synergistic anti-tumor effects of comprehensive tumor microenvironment remodeling and enhanced αPD-L1 efficacy, which offers a promising avenue for cancer immunotherapy. A tumor membrane-coated nanoplatform (P/A@MnO 2 -M) enables co-delivery of two functional proteins to induce ICD and suppress efferocytosis. This strategy ensures precise tumor killing, prolongs danger signal exposure, avoids immune cell damage, and preserves antigen-presenting processes. By supporting sustained DAMPs release and CD8 + T cell activation, it achieves full-course immune activation to remodel the immunosuppressive microenvironment in cold tumors. Download: Download high-res image (196KB) Download: Download full-size image
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