Journal of Controlled Release最新文献

{"title":"Ultrasound-triggered topical oxygen delivery enhances synergistic sonodynamic and antibody therapies against hypoxic gastric cancer","authors":"Xinxin Xie ,&nbsp;Jinxia Zhang ,&nbsp;Lihong Sun ,&nbsp;Shuyu Xu ,&nbsp;Shiti Sha Ma ,&nbsp;Haonan Wang ,&nbsp;Xiaoda Li ,&nbsp;Qiong Xiang ,&nbsp;Ligang Cui ,&nbsp;Xiaolong Liang","doi":"10.1016/j.jconrel.2025.02.019","DOIUrl":"10.1016/j.jconrel.2025.02.019","url":null,"abstract":"<div><div>Hypoxia is a common feature of malignant tumors, which can accelerate tumor growth and reduce the sensitivity of chemotherapy and sonodynamic therapy by activating the hypoxia-inducible factor (HIF) signaling pathway. In HER2-positive gastric cancer, HER2 overexpression enhances HIF-1α synthesis, exacerbating hypoxia and impairing sonodynamic therapy. It also reduces trastuzumab-mediated antibody-dependent cytotoxicity, significantly compromising therapeutic outcomes. Herein, pyropheophorbide-conjugated lipid (pyropheophorbide-lipid, PL) and trastuzumab were fabricated into targeted nanoparticles (TP NPs) for loading perfluorobromooctane (PFOB) carrying oxygen (TPPO NPs), thus enabling oxygen self-supplied sonodynamic and antibody therapies. <em>In vitro</em> experiments showed that antibody targeting significantly increased the cellular uptake of sonosensitizers, and the controlled release of oxygen was dependent on ultrasound parameters, greatly enhancing the killing effects of SDT and antibody therapy. <em>In vivo</em> animal experiments showed that TPPO NPs-mediated enhanced permeation and retention (EPR) effects, along with antibody targeting, improved the enrichment of sonosensitizers in tumors. Notably, ultrasound-triggered topical delivery of oxygen significantly alleviated tumor hypoxia and further improved the efficacy of SDT and antibody therapy. Given the good biosafety profile of TPPO NPs, this system holds great promise for future clinical applications in gastric cancer.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 736-750"},"PeriodicalIF":10.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phage-inspired targeting of antibiotic-loaded polymeric micelles for enhanced therapeutic efficacy against monomicrobial sepsis","authors":"Tulin Ozbek ,&nbsp;Hatice Demir ,&nbsp;Senanur Dokuz ,&nbsp;Semra Tasdurmazli ,&nbsp;Utku Ozbey ,&nbsp;Mehmet Ozbil ,&nbsp;Murat Topuzogullari ,&nbsp;Irfan Cinar ,&nbsp;Murat Karamese ,&nbsp;Selina Aksak Karamese ,&nbsp;Serap Acar ,&nbsp;Omer Faruk Bayrak ,&nbsp;Elif Cadirci","doi":"10.1016/j.jconrel.2025.02.035","DOIUrl":"10.1016/j.jconrel.2025.02.035","url":null,"abstract":"<div><div>The rapid increase in bacterial resistance to existing treatments underscores the critical need for novel therapeutic strategies. Here, an innovative approach using targeted nanocarrier systems that mimic phage-bacteria interactions through phage receptor binding protein (Gp45 from the ϕ11 lysogenic phage) or derived peptides (P1, P2, P3, P4, P5), are introduced. These nanodrugs, exhibited receptor-ligand specificity and strong binding affinity, for the first time, were employed for the precise delivery and targeting of antibiotics within living organisms. The actively targeted micelles via two methods were produced; conjugating GP45 to dual antibiotic-loaded PLGA-b-PEG micelles (MiGp45) and the synthesis of peptide-conjugated micelles with dual antibiotic-loaded PLGA-b-PEG-peptide triblock copolymers. The untargeted nano-drug reduced MIC values by 2–10 times for vancomycin and 9–75 times for oxacillin, resulting in a synergistic effect. MiGp45 and MiP1-targeted micelles further reduced MIC values at least twofold, up to ninefold in resistant strains, indicating significant antibacterial improvement. In a mouse model of sepsis by <em>S. aureus</em>, MiGp45 treatment resulted in complete recovery as opposed to death in the untreated group, significantly reduced bacterial load, pro-inflammatory cytokine expression, lung injury, and normalized oxidative stress. The phage-based nanodrugs show tremendous promise as a highly effective antimicrobial treatment targeting multidrug- resistant pathogens.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 773-786"},"PeriodicalIF":10.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancement and characterization of nanoparticle diffusion in biological tissues by magnetic heating and oscillation","authors":"Xilong Zhang ,&nbsp;Lingze Zhang ,&nbsp;Kai Yue ,&nbsp;Xiaotong Yan ,&nbsp;Xinxin Zhang ,&nbsp;Chang Yuan ,&nbsp;Lei Wang ,&nbsp;Hao Wang","doi":"10.1016/j.jconrel.2025.02.023","DOIUrl":"10.1016/j.jconrel.2025.02.023","url":null,"abstract":"<div><div>Given the unsatisfactory delivery efficiency of nanoagents to target lesions in biological systems, this study proposed a magnetic field regulation method aimed at boosting nanoparticle (NP) diffusion in porous tissues by leveraging both magneto-thermal effects and magnetic oscillation. <em>In vitro</em> experiments using pork liver tissues and <em>in vivo</em> experiments on fibrosarcoma tumors in mice were conducted. Our study achieved quantitative characterization of NP diffusion, detailing the temporal and spatial distribution of NPs. The results show that the improvement of intratumor NP diffusion driven by an oscillating magnetic field (30 mT, 15 Hz), was notably greater than that due to the magneto-thermal effect from a high-frequency alternating magnetic field (27 kA/m, 115 kHz). Under magnetic oscillation, the overall diffusivity of the NPs in fibrosarcoma tumors was 4.45 times greater than that under untreated conditions. NP diffusivity decreased with increasing diffusion time and length due to the concentration dependence of diffusivity and was strongly influenced by tissue structure.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 725-735"},"PeriodicalIF":10.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tolerogenic nanovaccines for the treatment of type I allergic diseases","authors":"Yuxuan Ren ,&nbsp;Daoke Yao ,&nbsp;Fang Wu ,&nbsp;Jing Xiao ,&nbsp;Lixia Ma ,&nbsp;Yong Zhang ,&nbsp;Zhihui Zhang ,&nbsp;Guangjie He ,&nbsp;Wengjing Deng ,&nbsp;Bo Qin ,&nbsp;Ningjing Lei ,&nbsp;Fazhan Wang","doi":"10.1016/j.jconrel.2025.02.029","DOIUrl":"10.1016/j.jconrel.2025.02.029","url":null,"abstract":"<div><div>The high prevalence of type I allergic diseases such as allergic rhinitis, allergic asthma, food allergies, allergic conjunctivitis, and atopic dermatitis has emerged as a significant public health concern globally. Failure of immune tolerance to ordinarily harmless substances or stimulation, and subsequent induction of T helper 2 cells by antigen-presenting cells evokes the allergic immune response, which results in persistent inflammation, tissue damage, and organ function impairment. Current therapeutic approaches for allergic diseases include avoiding allergen exposure, corticosteroids, biologics, etc. However, these strategies only relieve allergic symptoms but hardly prevent the deteriorative progression and may have adverse effects on patients. With the rapid development of nanotechnology and immunology, emerging tolerogenic nanovaccines represent novel approaches with the potential to cure type I allergic diseases rather than merely alleviate symptoms. In this review, we expound the burgeoning field of tolerogenic nanovaccines against type I allergic diseases, highlight various types of antigens employed in constructing allergen extracts, protein/peptide and nucleic acid-based tolerogenic nanovaccines, and discuss their application in allergic rhinitis, allergic asthma, food allergies, allergic conjunctivitis, and atopic dermatitis.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 664-685"},"PeriodicalIF":10.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143420367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioactive hydrogel formulations for regeneration of pathological bone defects","authors":"Zuhao Li ,&nbsp;Kaixuan Ren ,&nbsp;Jiajia Chen ,&nbsp;Yaling Zhuang ,&nbsp;Shujun Dong ,&nbsp;Jincheng Wang ,&nbsp;He Liu ,&nbsp;Jianxun Ding","doi":"10.1016/j.jconrel.2025.01.061","DOIUrl":"10.1016/j.jconrel.2025.01.061","url":null,"abstract":"<div><div>Bone defects caused by osteoporosis, infection, diabetes, post-tumor resection, and nonunion often cause severe pain and markedly increase morbidity and mortality, which remain a significant challenge for orthopedic surgeons. The precise local treatments for these pathological complications are essential to avoid poor or failed bone repair. Hydrogel formulations serve as injectable innovative platforms that overcome microenvironmental obstacles and as delivery systems for controlled release of various bioactive substances to bone defects in a targeted manner. Additionally, hydrogel formulations can be tailored for specific mechanical strengths and degradation profiles by adjusting their physical and chemical properties, which are crucial for prolonged drug retention and effective bone repair. This review summarizes recent advances in bioactive hydrogel formulations as three-dimensional scaffolds that support cell proliferation and differentiation. It also highlights their role as smart drug-delivery systems with capable of continuously releasing antibacterial agents, anti-inflammatory drugs, chemotherapeutic agents, and osteogenesis-related factors to enhance bone regeneration in pathological areas. Furthermore, the limitations of hydrogel formulations in pathological bone repair are discussed, and future development directions are proposed, which is expected to pave the way for the repair of pathological bone defects.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 686-714"},"PeriodicalIF":10.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting human subcutaneous bioavailability of monoclonal antibodies using an integrated in-vitro/in-silico approach","authors":"Belal I. Hanafy ,&nbsp;Isabelle Trayton ,&nbsp;Monika Sundqvist ,&nbsp;Jenna Caldwell ,&nbsp;Neil Mody ,&nbsp;Katie Day ,&nbsp;Mariarosa Mazza","doi":"10.1016/j.jconrel.2025.02.022","DOIUrl":"10.1016/j.jconrel.2025.02.022","url":null,"abstract":"<div><div>Monoclonal antibodies (mAbs) have become a cornerstone in therapeutic development, increasingly administered via subcutaneous (SC) injection due to its convenience and patient adherence benefits. However, accurately predicting SC bioavailability in humans remains a challenge, largely due to the limitations of traditional animal models that fail to provide reliable predictions for clinical outcomes, creating a significant gap in preclinical evaluations. To address this, we have developed an integrated <em>in-vitro</em>/<em>in-silico</em> approach that employs functional principal component analysis (FPCA) to summarize the release and transmission profiles information generated by the Subcutaneous Injection Site Simulator (SCISSOR) platform. The FPCA method extracted main shape functions from SCISSOR profiles, representing the most significant variations, and the resulting FPC scores were used as predictors in the modelling process. We employed self-validated ensemble modelling (SVEM) to predict the SC human bioavailability of mAbs based on the transmission and release features. SVEM is an ensemble modelling technique allowing the use of all observations for both training and validation making it a suitable method for small sample sizes. The model was further tested on new four commercial mAbs, demonstrating a good agreement between the predicted and actual bioavailability, and outperforming monkey data. We then elucidated how SCISSOR release and transmission profile are correlated with different mAbs and formulation parameters. This approach represents valuable addition to the toolkit for predicting the SC human bioavailability of mAbs. By combining <em>in-vitro</em> and <em>in-silico</em> methods, we offer a reliable approach that can outperform preclinical animal models.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 715-724"},"PeriodicalIF":10.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cotadutide reversible self-assembly based long-acting injectable depot for sustained delivery of GLP-1 glucagon receptor agonists with controlled burst release","authors":"Bin Yang ,&nbsp;Durga Devalla ,&nbsp;Silvia Sonzini ,&nbsp;Mikael Boberg ,&nbsp;Sashi Gopaul ,&nbsp;Monika Sundqvist ,&nbsp;Iain Grant ,&nbsp;Christopher Jones ,&nbsp;Stephanie Brookes ,&nbsp;Cindy Weidauer ,&nbsp;Eleonora Paladino ,&nbsp;Najet Mahmoudi ,&nbsp;Jason van Rooyen ,&nbsp;Ana Gomes dos Santos ,&nbsp;Johanna Laru ,&nbsp;Andy Campbell ,&nbsp;Lutz Jermutus ,&nbsp;Annette Bak","doi":"10.1016/j.jconrel.2025.01.064","DOIUrl":"10.1016/j.jconrel.2025.01.064","url":null,"abstract":"<div><div>Cotadutide (Cota) is a lipidated dual GLP-1 and Glucagon receptor agonist that was investigated for the treatment of various metabolic diseases, it is designed for once daily subcutaneous (SC) administration. <!--> <!-->Invasive daily injections can result in poor patient compliance with chronic disease, and here, we demonstrate an innovative strategy of encapsulating reversible cota self-assembled fibers within an in-situ forming depot of low molecular weight poly(lactic-<em>co</em>-glycolic) acid (LWPLGA) for sustained delivery GLP-1 and Glucagon receptor agonist with controlled burst release. This could be a suitable alternative to other sustained delivery strategies for fibrillating peptides. We investigated a range of cationic ions (Na⁺, Ca²⁺, Zn²⁺) and studied their influence on the secondary structure, morphology and the monomer release profile of cota fibers. Fibers forming hierarchy structures such as twisted filament and ribbons with beta sheet secondary structure resulted in better controlled burst. The subcutaneous administration of Ca²⁺ fiber/LWPLGA depot formulation in rats resulted in 60-fold reduction in maximum concentration (Cmax) compared with cota immediate release (IR) SC formulation and a prolonged plasma exposure over a month with plasma half-life extended from the 10 h observed with the cota daily formulation to 100 h. This extended-release formulation also maintains smaller peak and trough fluctuation within therapeutic window, and PK modelling of repeated dose indicates this formulation could enable a possible dose frequency of 14 days in rat with assumed therapeutic concentration (ratios of the maximum concentration and the trough concentration) C_max/C_trough window. This new long-acting injectable (LAI) method could open the door to transforming short-life peptides with sub-optimal half-life into candidates for weekly or even monthly dosing regimens, potentially leading to novel drug products with increased patient comfort.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 647-663"},"PeriodicalIF":10.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D mesenchymal stem cell exosome-functionalized hydrogels for corneal wound healing","authors":"Yuehe Xu ,&nbsp;Chao Wei ,&nbsp;Li Ma ,&nbsp;Long Zhao ,&nbsp;Dongfang Li ,&nbsp;Yiliang Lin ,&nbsp;Qingjun Zhou ,&nbsp;Lixin Xie ,&nbsp;Fuyan Wang","doi":"10.1016/j.jconrel.2025.02.030","DOIUrl":"10.1016/j.jconrel.2025.02.030","url":null,"abstract":"<div><div>Mesenchymal stem cell (MSC)-derived exosomes have the potential to sustain immune homeostasis and facilitate tissue regeneration, and those effects can be potentiated under three-dimensional (3D) cell culture conditions. Nevertheless, whether exosomes derived from 3D-cultured MSCs (3D-Exos) exert therapeutic effects on the injured corneas and the underlying mechanism remain unclear. In this study, MSCs are cultured in a gelatin methacryloyl (GelMA) hydrogel to produce 3D-Exos. <em>In vitro</em> experiments revealed that the 3D-cultured MSCs maintained their stemness, the exosomes were produced in better yield, and the generated 3D-Exos possess exceptional anti-inflammatory, pro-proliferative and tissue remodeling properties. Moreover, the 3D-Exos that were delivered by the GelMA hydrogel displayed a sustained release profile for multi-dimensional injured cornea repair. Extensive <em>in vitro</em> studies further demonstrated that, compared with the two-dimensional (2D)-Exo-hydrogel treatment, 3D-Exo-hydrogel treatment yielded better recovery of corneal morphology and function, as revealed by mitigated inflammation, promoted corneal epithelium and limbus repair, and reduced scar formation in the stroma. Mechanistically, the 3D-Exos promoted the proliferation of cornea-derived cells and reduced the release of inflammatory factors <em>via</em> miR-150-5p targeting of the PDCD4 gene. Overall, the developed 3D-Exo-hydrogel sustained release system may represent a promising cell-free strategy for the treatment of various corneal diseases.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 630-646"},"PeriodicalIF":10.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyphenol-based pH-responsive nanoparticles enhance chemo-immunotherapy in pancreatic cancer","authors":"Jieru Li ,&nbsp;Yiwei Dai ,&nbsp;Tao Wang ,&nbsp;Xinyu Zhang ,&nbsp;Pengcheng Du ,&nbsp;Yuman Dong ,&nbsp;Zuoyi Jiao","doi":"10.1016/j.jconrel.2025.02.021","DOIUrl":"10.1016/j.jconrel.2025.02.021","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is challenging to treat due to its difficulty in early diagnosis, highly invasive nature, and high metastatic potential. Currently, the primary treatments for PDAC are chemotherapy and immunotherapy. However, the abundance of extracellular matrix and immunosuppressive cells in the tumor microenvironment (TME) severely impedes the effectiveness of chemotherapy and immunotherapy, promoting tumor growth and metastasis. Indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive tryptophan-metabolizing enzyme, is upregulated in PDAC and degrades tryptophan (Trp) into kynurenine (Kyn), which is toxic to effector T cells and induces regulatory T cells (Treg) recruitment. Herein, we propose a concise strategy to construct a biocompatible, polyphenol-based, pH-responsive nanoparticle to co-deliver docetaxel (DTX) and NLG919 (an IDO1 inhibitor) to significantly enhance chemo-immunotherapy for PDAC by remodeling the TME. The DTX/NLG919-loaded nanoparticles (FPND) effectively elicited immunogenic cell death (ICD) in PDAC cells while limiting immunosuppressive Kyn production through IDO1 inhibition. FPND triggered an effective anti-tumor immune response, characterized by increased CD8⁺ T cells infiltration and decreased Treg recruitment, leading to significant inhibition of subcutaneous tumor growth in KPC mice through a combination of chemotherapy and immunotherapy. Overall, FPND nanoparticles showed excellent anti-tumor efficacy as a PDAC therapeutic strategy with broad potential in precision medicine.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 615-629"},"PeriodicalIF":10.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Injectable hydrogel microspheres promoting inflammation modulation and nucleus pulposus-like differentiation for intervertebral disc regeneration","authors":"Yuhang Chen ,&nbsp;Zhuo-Ran Yang ,&nbsp;Zhangrong Cheng ,&nbsp;Pengzhi Shi ,&nbsp;Anran Zhang ,&nbsp;Jing-Wen Fan ,&nbsp;Zhiguo Zhao ,&nbsp;Hao Jiang ,&nbsp;Jintao Zhu ,&nbsp;Yukun Zhang","doi":"10.1016/j.jconrel.2025.02.016","DOIUrl":"10.1016/j.jconrel.2025.02.016","url":null,"abstract":"<div><div>Local inflammation modulation and stem cell therapy have attracted much attention in the treatment of intervertebral disc degeneration (IDD). However, severe oxidative stress and limited nucleus pulposus (NP)-like differentiation of stem cells largely impair biomaterial implantation's therapeutic efficacy. Due to their excellent performance in injectability and flowability, and minor compression to NP tissue, hydrogel microspheres have become an attractive carrier for IDD treatment. Herein, an injectable hydrogel microsphere consisting of Wnt5a-mimetic peptide Foxy5- and the antioxidative peptide-grafted gelatin methacryloyl matrix (GFA), was developed as a stem cell delivery system for IDD therapy. Being fabricated and encapsulating bone marrow-derived mesenchymal stem cells (BMSCs) using the microfluidic technology, GFA hydrogel microspheres ameliorate IDD by promoting inflammation inhibition, NP-like differentiation and extracellular matrix regeneration. They efficiently eliminated reactive oxygen species, and downregulated the inflammation level through the inhibition of interleukin-17B/nuclear factor-κB signaling pathway. Moreover, the NP-like differentiation of BMSCs was effectively stimulated by Foxy5 <em>via</em> the calcium/calmodulin dependent protein kinase kinase 2/protein kinase A/sex determining region Y box protein 9 signaling pathway, thereby leading to a rebalance between the generation and degradation of NP matrix. <em>In vivo</em> rat IDD model demonstrated that BMSC-loaded GFA hydrogel microspheres mitigated local inflammation, preserved disc height, and promoted intervertebral disc regeneration. In conclusion, this study introduces an BMSC-loaded injectable hydrogel microspheres as a promising therapy for regulating the microenvironment and alleviating the progression of IDD.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 599-614"},"PeriodicalIF":10.5,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}