JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·737
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IF 12.6
Zheng Shuting,Zheng Yinfei,Hu Honglei,Liu Minyi,He Chenxi,Wu Zede,Hou Meirong,Liu Guoqiang,Xu Yikai,Yan Chenggong,Zhao Bingxia
Background The efficacy of radiotherapy (RT) is often compromised by tumor radioresistance and an immunosuppressive microenvironment. Two key limitations are the clearance of apoptotic cells (efferocytosis), which can promote an immunosuppressive phenotype, and the acidic tumor microenvironment (TME) that further restrains antitumor immunity. An ideal radiosensitizer should not only enhance radiation-induced cell death but also address these immunological barriers to unlock robust systemic antitumor immunity. Methods We constructed a multifunctional nano-system based on mesoporous organosilicon (HMON) as a template. Leveraging the tunability of the -Si-O-Si- framework, we incorporated manganese (Mn) and calcium (Ca) elements to form a unique –Si–O–M– hybrid structure (M = Mn or Ca). This composite was subsequently loaded with Omeprazole sodium (PPI) and efferocytosis inhibitor, and the surface was modified with hyaluronic acid (HA) for active targeting. In vitro, the radiosensitizing mechanism was investigated in 4T1 cells via western blot, immunofluorescence and flow cytometry. In vivo efficacy was evaluated in 4T1 tumor-bearing BALB/c mice following combined nano-system and RT treatment. Results The resulting nano-system exhibited a high T1 relaxivity (r1 = 8.95 mM⁻¹s⁻¹). In vitro and in vivo studies demonstrated that it significantly enhanced radiation-induced oxidative stress and mitochondrial dysfunction. The combination therapy achieved a remarkable ~ 96% tumor growth inhibition in 4T1 tumor-bearing mice. Crucially, it potentiated immunogenic cell death and activated the cGAS-STING pathway, evidenced by a > 3-fold increase in mature dendritic cells (DCs) and a > 4-fold enhancement in tumor-infiltrating cytotoxic T lymphocytes. Conclusion This study presents a novel “ion-interference amplifier” strategy that concurrently enhances radiosensitization and immune response, offering a powerful model for synergistic radio-immunotherapy. Meanwhile, the integration of MRI-based tracking further underscores its potential for clinical translation. Graphical
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BIOMATERIALS
·
2026
·
IF 13.6
Jinhu Zhao,Di An,Xiayan Yang,Qifeng Yu,Ke Kang,Qiangying Yi,Yao Wu
Atherosclerosis remains a leading contributor to cardiovascular mortality, driven primarily by defective efferocytosis and subsequent inflammatory within vulnerable plaques. Conventional therapeutic approaches often lack the specificity to simultaneously promote clearance of apoptotic cells and modulate pro-inflammatory signaling. In this study, we presented a biomimetic nanoplatform that enhances efferocytosis through dual-pathway regulation. This platform co-delivers phosphatidylserine (PS) to provide an "eat me" signal and InVivoMAb anti-mouse CD47 (aCD47) to block the "don't eat me" pathway. Constructed on a fluorescent silica nanosphere core camouflaged with immune cell membranes, this system enables precise targeting of atherosclerotic lesions. In vitro experiments confirmed the platform significantly enhanced macrophage phagocytosis (by 265%) and attenuated inflammatory responses, while exhibiting no detectable cytotoxicity. In vivo evaluation in an atherosclerotic mouse model demonstrated significant attenuation of plaque progression and increased plaque stability. Our findings underscore the potential of this dual-signal-modulating nanoplatform as a theranostic strategy for atherosclerosis that offers synchronized therapeutic and imaging capabilities.
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PHYTOMEDICINE
·
2026
·
IF 8.3
Yingying Xie,Haoming He,Yike Li,Qiang Chen,Sunjing Fu,Zhe Wang,Gaiyan Feng,Yanping Li,YanXiang Gao,Jingang Zheng
Background Heart failure with preserved ejection fraction (HFpEF) constitutes over 50% of heart failure cases but lacks disease-modifying therapies. The pathophysiological role of eicosapentaenoic acid (EPA) in HFpEF remains undefined. Methods Integrated lipidomics was conducted across HFpEF discovery and validation cohorts. "Two-hit" murine HFpEF model combining high-fat diet (HFD) and 0.5g/L L-NAMEwas established to recapitulate human metabolic-inflammatory pathology. EPA’s efficacy was evaluated through prophylactic/therapeutic interventions (160/320 mg/kg/day, human-equivalent 2/4 g/day). Mechanistic studies integrated transcriptomics, molecular docking, triggering receptor expressed on myeloid cells 2 (TREM2) knockout, and siRNA silencing. Results Plasma EPA deficiency correlated with diastolic dysfunction severity and conferred incremental diagnostic value. High-dose EPA (4 g/day equivalent) prevented/reversed diastolic impairment and apoptosis in HFpEF mice. EPA rescued impaired efferocytosis through dual modulation of TREM2, concurrently enhancing functional transmembrane receptor expression while suppressing pathological ectodomain shedding. TREM2 ablation attenuated EPA-mediated benefits on diastolic function and efferocytosis. Conclusion Our work identifies plasma EPA depletion as a potential biomarker for risk stratification and delineates the EPA-TREM2-efferocytosis axis as a putative therapeutic mechanism for HFpEF, suggesting the potential of EPA as a theranostic candidate.
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CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Linbang Wang,Rui Dou,Yunlong Ma,Jiayu Zhang,Xiaomeng Cai,Jinkun Liu,Xiaoguang Liu,Jun Chen
The immunosuppressive microenvironment (TME) of osteosarcoma (OS) results in an unsatisfactory conventional therapeutic effect. Conventional chemotherapy-induced apoptosis is unsuccessful to fully activate anti-tumor immunity as it fails to release Tumor-Associated Antigens (TAAs) and promotes efferocytosis of Tumor-Associated Macrophages (TAMs). In this study, we propose to remodel TME by inducing OS cells to immunogenic cell death, including pyroptosis and necroptosis induced by efferocytosis inhibition of TAMs. Specifically, we constructed a piezoelectric catalyst, BFO@CaO₂-TPP (BCT), which targets mitochondria. Under ultrasound, BCT generated reactive oxygen species (ROS) by enhancing the Fenton reaction and released Ca 2+ to trigger mitochondrial calcium overload, which synergistically activated the caspase-3/GSDME nonclassical pyroptosis pathway and prompted the release of proinflammatory molecules from tumor cells. At the same time, BCT disrupts mitochondrial oxidative phosphorylation (OXPHOS) in TAMs, inhibits their efferocytotic capacity. More importantly, TAMs facilitate the elevation of the GSDME express and TNF/TNFR1 interaction in osteosarcoma cells, favoring pyroptosis and necroptosis. Simultaneous endogenous and exogenous regulation is ultimately transforms the ‘cold’ TME into a ‘hot’ state. Patient-derived organoid-based validation confirmed the translational potential of this strategy.
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iScience
·
2026
·Vol. 29
·期 10
·117739
·
IF 4.5
Lingxi Meng,Rongpu Liu,Siyi Wang,Junyi Wang,Ilya A. Vinnikov,Rong Yang,Xinyu Song,Hongming Zhang,Jiajia Wang,Wenjie Zhang
Apoptosis at bone defects drives an anti-osteogenic oxidative stress environment • IL-4 drives a pro-reparative macrophage phenotype and upregulates the Arg1 pathway • Exogenous Arg fuels efferocytosis and secretion of pro-regenerative factors • Co-delivery of IL-4 and Arg via injectable hydrogel accelerates bone regeneration Summary Host bone microenvironment is a critical factor for successful bone regeneration during implantation. In this work, we identified a spatiotemporal mismatch at drilling-induced injury sites where initial apoptosis outpaces macrophage recruitment, leading to apoptotic cell accumulation and oxidative stress that impairs osteogenic differentiation. To mitigate this phenomenon, we developed a synergistic strategy co-delivering interleukin 4 (IL-4) and arginine (Arg) to reprogram the microenvironment. Mechanistically, IL-4 recruits and polarizes macrophages toward a pro-reparative M2 phenotype, while Arg fuels the arginase-1 metabolic pathway to sustain continual efferocytosis and secretion of pro-regenerative cytokines. In a mouse bone injury model, transcriptomic and histological analyses confirmed that this strategy accelerates apoptotic clearance and establishes an M2-dominant environment, significantly enhancing early bone regeneration. Altogether, this work proposes a novel therapeutic paradigm targeting macrophage efferocytosis to resolve early microenvironmental imbalances, providing a promising therapeutic approach to promote bone defect healing and offering novel insights into optimizing host microenvironments for osseointegration following implantation. Download: Download high-res image (245KB) Download: Download full-size image
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BIOMATERIALS
·
2026
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IF 13.6
Yuxin Qian,Wentao Wang,Mingzhe Xin,Haonan Ding,Yi Shuai,Zelong Hu,Xuwen Wang,Shijia Huang,Rui Mu,Ming Zhang,Lei Jin
Radiotherapy for head and neck cancer frequently induces severe radiation-induced oral mucositis (RIOM), in which excessive reactive oxygen species (ROS), defective macrophage efferocytosis, and persistent inflammation form a self-amplifying pathological loop that delays mucosal repair. Current symptomatic treatments are insufficient to simultaneously suppress oxidative stress and restore immune-mediated clearance of damaged cells. Here, we developed a detachable microneedle patch with ROS-responsive tips (PTC MN) for localized in situ macrophage programming within RIOM lesions. The PTC MN was fabricated from a PPBA-TA-PVA hydrogel matrix, which combines intrinsic ROS-scavenging capacity with oxidative stress triggered degradation, and loaded with engineered hybrid nanovesicles (HLENs-CAR) carrying a plasmid encoding CAR-ectoCRT-IL-4. This design enabled local delivery of gene-loaded nanovesicles, macrophage-targeted genetic programming, and sustained retention of the therapeutic payload in the injured mucosa. In a murine RIOM model, PTC MN accelerated mucosal epithelial regeneration, reduced oxidative stress and inflammatory infiltration, enhanced reparative macrophage responses, and attenuated fibrosis-associated tissue remodeling. Functionally, the platform enhanced macrophage efferocytosis, promoted IL-4-associated reparative polarization, and shifted the lesion microenvironment toward inflammation resolution and tissue regeneration. Collectively, this study establishes a smart in situ immunomodulation strategy that integrates ROS-responsive microneedle delivery with CAR-macrophage programming, providing a potential therapeutic paradigm for refractory mucosal injury.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Hongwei Xiong,Xuan Li,Shaopeng Liu,Qiaojian Duan,Zixuan Wang,Xiao Jiang,Song Liu,Peng Liu,Kaiyong Cai
A smart-responsive implant coating was developed to regulate innate immunity for enhanced bone regeneration in diabetes. • Phenylboronic ester bonds link the titanium platform with drug-loaded particles, enabling smart-triggered drug release. • Hyaluronic acid-based microparticles (HPP@Cur) ensure precise delivery and improve the state of injured macrophages. • The immune microenvironment is effectively reshaped, actively guiding biomineralization and bone regeneration. Diabetes mellitus (DM) creates a chronic inflammatory microenvironment that severely compromises osseointegration, the key to implant success. This impairment is largely driven by hyperglycemia-induced metabolic disturbances, which trigger oxidative stress and mitochondrial dysfunction in immune cells. Efferocytosis, the macrophage-mediated clearance of apoptotic cells, is a crucial self-resolving anti-inflammatory process. Herein, we developed a smart drug-delivery system on the surface of titanium (Ti) implant for reactivating macrophage function by promoting efferocytosis. Hyaluronic acid (HA) grafted with phenylboronic acid (PBA), poly- l -lysine (PLL) and curcumin (Cur) were assembled into HPP NPs (HA-PBA-PLL nanoparticles). The NPs were anchored to a polydopamine-coated Ti implant via reversible PBA ester linkages. Upon implantation into a diabetic bone defect with high ROS levels, these linkages underwent rapid cleavage, triggering the on-demand release of NPs. Following release, HA-mediated CD44 receptor recognition enabled preferential macrophage targeting and cellular uptake. Subsequent exposure to the acidic environment of the endosome/lysosome induced NPs degradation and Cur release. This targeted delivery would synergistically enhance efferocytosis, thereby reprogramming macrophages, restoring immune homeostasis, and ultimately promoting osseointegration in a diabetic microenvironment. This approach offers a novel therapeutic strategy for resetting immune function and breaking the chronic inflammatory cycle to improve osseointegration of the implant in DM.
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Zhiwen Wang,Ge Xie,Yue Xie,Mingcun Hu,Qiao Hu,Min Yang,Lianbin Zhang,Jintao Zhu,Chun Zhang
Efferocytosis, the clearance of apoptotic cells, is an essential process for resolving inflammation. Current evidence suggests that in acute kidney injury (AKI), the inflammatory cascade triggered by oxidative stress in damaged tissues can impair efferocytosis. This disrupts the clearance of apoptotic cells, exacerbates inflammatory reactions, and ultimately leads to tissue damage. To address this challenge, we developed a novel renal dual-targeting nanoplatform for AKI treatment based on black phosphorus nanosheets (BPNSs). Surface modification with LTH and 4-Octyl itaconate (4OI) endowed BPNSs with both renal tubulars targeting specificity and sustained antioxidant properties. This nanoplatform could effectively target damaged renal tubular epithelial cells, scavenge excess reactive oxygen species (ROS), alleviate oxidative stress, enhance efferocytosis, inhibit inflammatory responses, and ultimately achieve the specific therapeutic goal of AKI.
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Nano Today
·
2025
·
IF 10.9
Danfeng Jian,Kai Ye,Limo Wang,Lulu Jin,Huang Yang,Lie Ma,Chenggang Yi,Zhengwei Mao,Jindan Wu
Improving efferocytosis of dendritic cells (DCs) by inhibiting membrane transporter protein SLC7A11 has been explored for healing diabetes wounds. However, the administration of SLC7A11 inhibitors has been linked to the generation of reactive oxygen species (ROS), which may compromise the viability and functionality of DCs. To mitigate this adverse effect, a nanozyme-loaded nanofiber dressing, termed GIPH, was developed. This dressing encapsulates a specific SLC7A11 inhibitor (HG106) in the core layer and incorporates an efficient nanozyme, Ir NPs-PVP, in the shell layer. The Ir NPs-PVP nanozyme effectively neutralizes ROS produced by HG106, thereby enhancing the viability of DCs and further promoting their efferocytosis. Our in vitro experiment results demonstrated that GIPH-treated Bone Marrow-Derived Dendritic Cells (BMDCs) exhibited a 1.68-fold increase in survival and a 1.52-fold enhancement in efferocytosis rate compared to those treated with HG106 alone. Furthermore, in a diabetic mouse wound model, the GIPH group showed superior healing outcomes, with wound nearly achieving complete recovery by day 12 (97.5 %). This research highlights the therapeutic potential of nanozyme-loaded nanofiber dressings while providing valuable insights for future investigations into the DCs-mediated wound healing process.
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Advanced Science
·
2024
·
IF 14.3
Shanshan Yuan,Yingqian Chai,Jianghua Xu,Youchao Wang,Lihua Jiang,Ning Lu,Hongyi Jiang,Jilong Wang,Xiaoyun Pan,Junjie Deng
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the synovial joints and the dysfunction of regulatory T cells (Tregs) in the peripheral blood. Therefore, an optimal treatment strategy should aim to eliminate the inflammatory response in the joints and simultaneously restore the immune tolerance of Tregs in peripheral blood. Accordingly, we developed an efferocytosis-mimicking nanovesicle that contains three functional factors for immunomodulating of efferocytosis, including “find me” and “eat me” signals for professional (macrophage) or non-professional phagocytes (T lymphocyte), and “apoptotic metabolite” for metabolite digestion. We showed that efferocytosis-mimicking nanovesicles targeted the inflamed joints and spleen of mice with collagen-induced arthritis, further recruiting and selectively binding to macrophages and T lymphocytes to induce M2 macrophage polarization and Treg differentiation and T helper cell 17 (Th17) recession. Under systemic administration, the efferocytosis-mimicking nanovesicles effectively maintained the pro-inflammatory M1/anti-inflammatory M2 macrophage balance in joints and the Treg/Th17 imbalance in peripheral blood to prevent RA progression. This study demonstrates the potential of efferocytosis-mimicking nanovesicles for RA immunotherapy.
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MATERIALS & DESIGN
·
2023
·
IF 8.4
Peidong You,Anning Yang,Yue Sun,Hongwen Zhang,Yaling Zeng,Yinju Hao,Jiantuan Xiong,Shengchao Ma,Huiping Zhang,Bin Liu,Yideng Jiang
Atherosclerosis is chronic inflammatory disease tightly related with defective efferocytosis of apoptotic cells (ACs) in the plaques. The strategy of efferocytosis reactivation using Atorvastatin (AT) and Metformin (Met) has attracted increasing attention for atherosclerosis treatment. Although these drug-based therapies could stimulate the phagocytic clearance of ACs, the rapid drug clearance and poor bioavailability limited their efficacy. In this study, by co-loading AT and Met into poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs), we developed a biomimetic nanocomplexes for targeted atherosclerosis treatment. Macrophages membrane-coated nanocomplexes efficiently avoided the clearance of NPs from immune system and achieved targeting ability to the atherosclerotic plaques. Moreover, modified hyaluronic acid (HA) delivered NPs into the dysfunctional efferocytic cells of plaques, and achieved the plaques-macrophages-targeted therapy. In vitro results indicated that the biomimetic nanocomplexes reactivated efferocytosis by facilitating macrophages polarization from M1 to M2 phenotype through enhancing ERK5/MerTK pathway and inhibiting cellular senescence through inhibiting p53-p16/pRB pathway. In vivo study indicated that this biomimetic nanocomplexes accumulated in the atherosclerotic plaques, resulting in reduction of necrotic core area and protection against plaque rupture by reactivating efferocytosis. These findings indicated that reactivation of efferocytosis by AT and Met co-delivered nanocomplexes provided a novel promising strategy for targeted atherosclerosis treatment.
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JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Xiong Liu,Xiangjun Ou,Tiantian Zhang,Xiaonan Li,Qi Qiao,Liyuan Jia,Zhangxi Xu,Fangming Zhang,Tianyi Tian,Hongbing Lan,Conglian Yang,Li Kong,Zhiping Zhang
In the progression of acute inflammation, the activation and recruitment of macrophages and neutrophils are mutually reinforcing, leading to amplified inflammatory response and severe tissue damage. Therefore, to regulate the axis of neutrophils and macrophages is essential to avoid tissue damage induced from acute inflammatory. Apoptotic neutrophils can regulate the anti-inflammatory activity of macrophages through the efferocytosis. The strategy of in situ targeting and inducing neutrophil apoptosis has the potential to modulate macrophage activity and transfer anti-inflammatory drugs. Herein, a natural glycyrrhiza protein nanoparticle loaded with dexamethasone (Dex@GNPs) was constructed, which could simultaneously regulate neutrophil and macrophage function during acute inflammation treatment by combining in situ neutrophil apoptosis and macrophage efferocytosis. Dex@GNPs can be rapidly and selectively internalized by neutrophils and subsequently induce neutrophils apoptosis through a ROS-dependent mechanism. The efferocytosis of apoptotic neutrophils not only promoted the polarization of macrophages into anti-inflammatory state, but also facilitated the transfer of Dex@GNPs to macrophages. This enabled dexamethasone to further modulate macrophage function. In mouse models of acute respiratory distress syndrome and sepsis, Dex@GNPs significantly ameliorated the disordered immune microenvironment and alleviated tissue injury. This study presents a novel strategy for drug delivery and inflammation regulation to effectively treat acute inflammatory diseases.
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