Pub Date : 2025-02-06DOI: 10.1016/j.jconrel.2025.01.072
Reaid Hasan , Zhen Zhao , Yuanke Li , Yanli Liu , Yuanyuan Zhang , Kun Cheng
Pancreatic cancer is one of the most aggressive malignancies with poor prognostic outcomes, necessitating the exploration of novel biomarkers and therapeutic targets for early detection and effective treatment. Small extracellular vesicles (sEVs) secreted by cells, have gained considerable attention in cancer research due to their role in intercellular communication and their potential as non-invasive biomarkers. This review focuses on the role of sEVs in the progression of pancreatic cancer and their application as biomarkers. We delve into the biogenesis, composition, and functional implications of sEVs in pancreatic tumor biology, emphasizing their involvement in processes such as tumor growth, metastasis, immune modulation, and chemotherapy resistance. In addition, we discuss the challenges in isolating and characterizing sEVs. The review also highlights recent advances in the utilization of sEV-derived biomarkers for the early diagnosis, prognosis, and monitoring of pancreatic cancer. By synthesizing the latest findings, we aim to underscore the significance of sEVs in pancreatic cancer and their potential to revolutionize patient management through improved diagnostics and targeted therapies.
{"title":"Small extracellular vesicles (sEVs) in pancreatic cancer progression and diagnosis","authors":"Reaid Hasan , Zhen Zhao , Yuanke Li , Yanli Liu , Yuanyuan Zhang , Kun Cheng","doi":"10.1016/j.jconrel.2025.01.072","DOIUrl":"10.1016/j.jconrel.2025.01.072","url":null,"abstract":"<div><div>Pancreatic cancer is one of the most aggressive malignancies with poor prognostic outcomes, necessitating the exploration of novel biomarkers and therapeutic targets for early detection and effective treatment. Small extracellular vesicles (sEVs) secreted by cells, have gained considerable attention in cancer research due to their role in intercellular communication and their potential as non-invasive biomarkers. This review focuses on the role of sEVs in the progression of pancreatic cancer and their application as biomarkers. We delve into the biogenesis, composition, and functional implications of sEVs in pancreatic tumor biology, emphasizing their involvement in processes such as tumor growth, metastasis, immune modulation, and chemotherapy resistance. In addition, we discuss the challenges in isolating and characterizing sEVs. The review also highlights recent advances in the utilization of sEV-derived biomarkers for the early diagnosis, prognosis, and monitoring of pancreatic cancer. By synthesizing the latest findings, we aim to underscore the significance of sEVs in pancreatic cancer and their potential to revolutionize patient management through improved diagnostics and targeted therapies.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 269-282"},"PeriodicalIF":10.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074764","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}
Pub Date : 2025-02-06DOI: 10.1016/j.jconrel.2025.02.002
Pengcheng Xiao , Junyan Liu , Chengcheng Du , Shengwen Cheng , Senrui Liu , Jiacheng Liu , Jingdi Zhan , Zhuolin Chen , Yaji Yang , Yiting Lei , Wei Huang , Chen Zhao
The disruption and limited reconstruction capacity of the osteocyte network are pivotal factors underlying impaired bone regeneration. This study developed an injectable mineralized hydrogel microsphere that provides a mineral-rich environment and optimal matrix stiffness for osteocyte network restoration. Furthermore, it spatially activates Notch signaling through osteocyte-derived vesicles with high Jagged1 expression, promoting osteocyte differentiation and enhancing angiogenic regulatory function. Specifically, hydrogel microspheres combining gelatin methacrylate (GelMA), alginate methacrylate (AlgMA), and osteocyte membrane vesicles (OMVs) were fabricated via gas-shear microfluidics and photopolymerization, followed by in situ pre-mineralization to produce mineralized microspheres. Findings indicate that mineralized hydrogel microspheres exhibit significantly increased compressive modulus and in situ formation of amorphous calcium phosphate particles within the gel matrix. In vitro, the mineralized microspheres effectively facilitated osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BMSCs), with adherent cells displaying accelerated osteocyte marker expression. Co-culture experiments further revealed enhanced vascular formation potential. Ectopic bone regeneration studies demonstrated that mineralized hydrogel microspheres promote rapid formation of mature osteocyte networks in vivo. Moreover, in a femoral critical bone defect model, these microspheres accelerated defect healing. Collectively, mineralized hydrogel microspheres expedite osteocyte network reconstruction, supporting intelligent bone regeneration, and present a promising approach for critical-sized bone defect repair.
{"title":"Injectable mineralized hydrogel microspheres for accelerated osteocyte network reconstruction and intelligent bone regeneration","authors":"Pengcheng Xiao , Junyan Liu , Chengcheng Du , Shengwen Cheng , Senrui Liu , Jiacheng Liu , Jingdi Zhan , Zhuolin Chen , Yaji Yang , Yiting Lei , Wei Huang , Chen Zhao","doi":"10.1016/j.jconrel.2025.02.002","DOIUrl":"10.1016/j.jconrel.2025.02.002","url":null,"abstract":"<div><div>The disruption and limited reconstruction capacity of the osteocyte network are pivotal factors underlying impaired bone regeneration. This study developed an injectable mineralized hydrogel microsphere that provides a mineral-rich environment and optimal matrix stiffness for osteocyte network restoration. Furthermore, it spatially activates Notch signaling through osteocyte-derived vesicles with high Jagged1 expression, promoting osteocyte differentiation and enhancing angiogenic regulatory function. Specifically, hydrogel microspheres combining gelatin methacrylate (GelMA), alginate methacrylate (AlgMA), and osteocyte membrane vesicles (OMVs) were fabricated via gas-shear microfluidics and photopolymerization, followed by in situ pre-mineralization to produce mineralized microspheres. Findings indicate that mineralized hydrogel microspheres exhibit significantly increased compressive modulus and in situ formation of amorphous calcium phosphate particles within the gel matrix. In vitro, the mineralized microspheres effectively facilitated osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BMSCs), with adherent cells displaying accelerated osteocyte marker expression. Co-culture experiments further revealed enhanced vascular formation potential. Ectopic bone regeneration studies demonstrated that mineralized hydrogel microspheres promote rapid formation of mature osteocyte networks in vivo. Moreover, in a femoral critical bone defect model, these microspheres accelerated defect healing. Collectively, mineralized hydrogel microspheres expedite osteocyte network reconstruction, supporting intelligent bone regeneration, and present a promising approach for critical-sized bone defect repair.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 240-255"},"PeriodicalIF":10.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191872","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}
Pub Date : 2025-02-06DOI: 10.1016/j.jconrel.2025.01.075
Ying Tang , Yang Chen , Yong-Dan Qi , Hui-Yi Yan , Wen-An Peng , Yu-Qiang Wang , Qian-Xiao Huang , Xin-Hua Liu , Jing-Jie Ye , Yun Yu , Xian-Zheng Zhang , Cui Huang
Biofilms increase bacterial resistance to antibiotics, as conventional antibiotic doses are often ineffective at penetrating the biofilm matrix to eliminate bacteria. Recent research has shown that the Gram-negative predator bacterium Bdellovibrio bacteriovorus can penetrate Gram-positive bacterial biofilms during its predation phase and benefit from them without direct predation. Here, based on the penetration ability of B. bacteriovorus, we constructed antibiotic-loaded liposome-engineered B. bacteriovorus as a drug delivery strategy for biofilm-related diseases. As a “living antibiotic,” B. bacteriovorus can prey on Gram-negative bacteria, penetrate biofilms, and disrupt their dense structure. During this process, the rapid movement of B. bacteriovorus enhances the delivery of antibiotic-loaded liposomes into the biofilm, promoting efficient antibiotic release and improving biofilm eradication. Our findings demonstrate that this engineered living antibiotic strategy significantly improves the control and removal of bacterial biofilms, accelerates the elimination of dental plaque, promotes wound healing, and holds promise as a novel platform for treating biofilm-related infections.
{"title":"Engineered Bdellovibrio bacteriovorus enhances antibiotic penetration and biofilm eradication","authors":"Ying Tang , Yang Chen , Yong-Dan Qi , Hui-Yi Yan , Wen-An Peng , Yu-Qiang Wang , Qian-Xiao Huang , Xin-Hua Liu , Jing-Jie Ye , Yun Yu , Xian-Zheng Zhang , Cui Huang","doi":"10.1016/j.jconrel.2025.01.075","DOIUrl":"10.1016/j.jconrel.2025.01.075","url":null,"abstract":"<div><div>Biofilms increase bacterial resistance to antibiotics, as conventional antibiotic doses are often ineffective at penetrating the biofilm matrix to eliminate bacteria. Recent research has shown that the Gram-negative predator bacterium <em>Bdellovibrio bacteriovorus</em> can penetrate Gram-positive bacterial biofilms during its predation phase and benefit from them without direct predation. Here, based on the penetration ability of <em>B. bacteriovorus</em>, we constructed antibiotic-loaded liposome-engineered <em>B. bacteriovorus</em> as a drug delivery strategy for biofilm-related diseases. As a “living antibiotic,” <em>B. bacteriovorus</em> can prey on Gram-negative bacteria, penetrate biofilms, and disrupt their dense structure. During this process, the rapid movement of <em>B. bacteriovorus</em> enhances the delivery of antibiotic-loaded liposomes into the biofilm, promoting efficient antibiotic release and improving biofilm eradication. Our findings demonstrate that this engineered living antibiotic strategy significantly improves the control and removal of bacterial biofilms, accelerates the elimination of dental plaque, promotes wound healing, and holds promise as a novel platform for treating biofilm-related infections.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 283-296"},"PeriodicalIF":10.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079920","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}
Pub Date : 2025-02-05DOI: 10.1016/j.jconrel.2025.01.086
Lin Yu , Lulu Gao , Bing Liang , Lu Zhang , Min Wu , Jingjing Liu
While sonodynamic therapy (SDT) has shown promise in treating triple-negative breast cancer (TNBC) due to its non-invasive nature, deep tissue penetration, and induction of immunogenic cell death (ICD), its efficacy remains limited by the complex immunosuppressive tumor microenvironment (TME). In this study, we developed tumor microenvironment-responsive nanoparticles (GdNPs) to enhance SDT effectiveness through epigenetic reprogramming of the TME by encapsulating the sonosensitizer chlorin e6 (Ce6) and the histone deacetylase 6 (HDAC6) inhibitor Ricolinostat (Ric) (GdNPs/Ce6-Ric). GdNPs/Ce6-Ric effectively accumulate at tumor sites via the enhanced permeability and retention (EPR) effect and release Ce6 and Ric in response to the acidic TME. Upon ultrasound stimulation, GdNPs/Ce6-Ric induce cancer cell apoptosis and trigger ICD by generating reactive oxygen species (ROS), which activate cytotoxic T cells and promote tumor cell elimination. Notably, the epigenetic modulation by Ric within the immunosuppressive TME increased the proportion of natural killer (NK) cells and cytotoxic T cells while decreasing the population of immunosuppressive regulatory T (Treg) cells. This modulation synergistically enhanced the anti-tumor effects of SDT by downregulating the HDAC6/p-STAT3/PD-L1 pathway. Furthermore, GdNPs/Ce6-Ric minimized lung metastases by not only improving systemic immune responses but also inhibiting TGFβ-induced epithelial-mesenchymal transition (EMT) of tumor cells through the blockade of α-tubulin deacetylation. Thus, GdNPs/Ce6-Ric-based epigenetic modulation of the immunosuppressive TME offers a promising approach to enhance the efficacy of SDT in treating TNBC.
{"title":"Polymer-based nanodrugs enhance sonodynamic therapy through epigenetic reprogramming of the immunosuppressive tumor microenvironment","authors":"Lin Yu , Lulu Gao , Bing Liang , Lu Zhang , Min Wu , Jingjing Liu","doi":"10.1016/j.jconrel.2025.01.086","DOIUrl":"10.1016/j.jconrel.2025.01.086","url":null,"abstract":"<div><div>While sonodynamic therapy (SDT) has shown promise in treating triple-negative breast cancer (TNBC) due to its non-invasive nature, deep tissue penetration, and induction of immunogenic cell death (ICD), its efficacy remains limited by the complex immunosuppressive tumor microenvironment (TME). In this study, we developed tumor microenvironment-responsive nanoparticles (GdNPs) to enhance SDT effectiveness through epigenetic reprogramming of the TME by encapsulating the sonosensitizer chlorin e6 (Ce6) and the histone deacetylase 6 (HDAC6) inhibitor Ricolinostat (Ric) (GdNPs/Ce6-Ric). GdNPs/Ce6-Ric effectively accumulate at tumor sites via the enhanced permeability and retention (EPR) effect and release Ce6 and Ric in response to the acidic TME. Upon ultrasound stimulation, GdNPs/Ce6-Ric induce cancer cell apoptosis and trigger ICD by generating reactive oxygen species (ROS), which activate cytotoxic T cells and promote tumor cell elimination. Notably, the epigenetic modulation by Ric within the immunosuppressive TME increased the proportion of natural killer (NK) cells and cytotoxic T cells while decreasing the population of immunosuppressive regulatory T (Treg) cells. This modulation synergistically enhanced the anti-tumor effects of SDT by downregulating the HDAC6/p-STAT3/PD-L1 pathway. Furthermore, GdNPs/Ce6-Ric minimized lung metastases by not only improving systemic immune responses but also inhibiting TGFβ-induced epithelial-mesenchymal transition (EMT) of tumor cells through the blockade of α-tubulin deacetylation. Thus, GdNPs/Ce6-Ric-based epigenetic modulation of the immunosuppressive TME offers a promising approach to enhance the efficacy of SDT in treating TNBC.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 125-137"},"PeriodicalIF":10.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074759","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}
Pub Date : 2025-02-05DOI: 10.1016/j.jconrel.2025.01.095
Norman L. Ilich , Siamak Saifzadeh , Dietmar W. Hutmacher , Tim R. Dargaville
The manufacturing of millimeter-sized implants for delayed drug release presents several challenges. However, it allows for the encapsulation of a therapeutic agent within a single device, enabling precise control over factors such as geometry, polymer composition, and drug formulation. The relatively large size, however, means that when inserted into subcutaneous tissue the implants experience mechanical stresses that are not predicted by current in vitro methods consisting of incubation under static conditions. The absence of a suitable in vitro assay complicates the device development process, often resulting in unsuccessful preclinical testing. This study presents the fabrication of flexible implants of poly(glycolide-co-trimethylene carbonate-co-ε-caprolactone), in vitro degradation, and performance when implanted subcutaneously in rats. Predicting the in vivo behaviour is addressed by the development of a scalable, high-throughput, cyclic flexural testing system. Flexural loading of the implant demonstrates a clear impact on loss in mechanical properties compared to static conditions in lipoprotein lipase. Under static conditions, a lag time of 60 days is observed before sustained release of the model dye. Conversely, the flexural loading assay results in early fracture by 20 days consistent with what is observed in the animal model. Decisively, this study emphasizes the importance of tailoring in vitro assays according to the dosage form and intended mode of administration. Implementation of a dynamic in vitro assay is invaluable to efficiently evaluate device viability and release kinetics and will, in turn, allow a more streamlined workflow for translation into preclinical models.
{"title":"Dynamic versus static testing and in vivo mechanical performance of poly(glycolide-trimethylene carbonate-ε-caprolactone) delayed release implants","authors":"Norman L. Ilich , Siamak Saifzadeh , Dietmar W. Hutmacher , Tim R. Dargaville","doi":"10.1016/j.jconrel.2025.01.095","DOIUrl":"10.1016/j.jconrel.2025.01.095","url":null,"abstract":"<div><div>The manufacturing of millimeter-sized implants for delayed drug release presents several challenges. However, it allows for the encapsulation of a therapeutic agent within a single device, enabling precise control over factors such as geometry, polymer composition, and drug formulation. The relatively large size, however, means that when inserted into subcutaneous tissue the implants experience mechanical stresses that are not predicted by current <em>in vitro</em> methods consisting of incubation under static conditions. The absence of a suitable <em>in vitro</em> assay complicates the device development process, often resulting in unsuccessful preclinical testing. This study presents the fabrication of flexible implants of poly(gly<em>co</em>lide-<em>co</em>-trimethylene carbonate-<em>co</em>-ε-caprolactone), <em>in vitro</em> degradation, and performance when implanted subcutaneously in rats. Predicting the <em>in vivo</em> behaviour is addressed by the development of a scalable, high-throughput, cyclic flexural testing system. Flexural loading of the implant demonstrates a clear impact on loss in mechanical properties compared to static conditions in lipoprotein lipase. Under static conditions, a lag time of 60 days is observed before sustained release of the model dye. Conversely, the flexural loading assay results in early fracture by 20 days consistent with what is observed in the animal model. Decisively, this study emphasizes the importance of tailoring <em>in vitro</em> assays according to the dosage form and intended mode of administration. Implementation of a dynamic <em>in vitro</em> assay is invaluable to efficiently evaluate device viability and release kinetics and will, in turn, allow a more streamlined workflow for translation into preclinical models.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 175-184"},"PeriodicalIF":10.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-muscle invasive bladder cancer (NMIBC) poses significant challenges due to its high recurrence rates and the difficulty in accurately distinguishing tumor lesions. Effective and economical methods for identifying cancerous tissues are urgently needed. In this study, we employed thiolated hollow mesoporous silica nanoparticles loaded with Evans blue (EB@HMSN(E)-SH), a traditional tumor staining dye, in conjunction with white light cystoscopy (WLC) to enhance the detection of bladder tumors. We observed that EB@HMSN(E)-SH exhibited mucoadhesive properties, demonstrating significant aggregation upon interaction with mucin, as assessed by the mucin-particle method using Dynamic Light Scattering (DLS). The permeation-enhancing capability of EB@HMSN(E)-SH was evaluated using tumor spheroid models. Despite repeated flushing, EB@HMSN(E)-SH adhered effectively to the mice bladder mucosa, aiding in the differentiation of tumor tissue from normal and inflammatory lesions, facilitated by the disordered structure of tumor tissue. Tissues stained with EB@HMSN(E)-SH showed co-localization with NBT-2 tumor cells expressing GFP, confirmed by confocal microscopy, which revealed deeper penetration of EB released from HMSN(E)-SH into bladder tumors compared to free EB. The combined use of WLC and EB@HMSN(E)-SH enabled precise identification of tumor-like tissues, corroborated by histopathological examination using H&E staining. The mucoadhesive properties and extended retention time of EB@HMSN(E)-SH complement WLC effectively in identifying NMIBC, suggesting its potential as a promising diagnostic tool.
{"title":"Precise identification of bladder tumors utilizing mucoadhesive thiolated hollow mesoporous silica nanoparticles.","authors":"Yu-Chen Fa, Cheng-Che Chen, Yi-Chun Liu, Yu-Huan Lu, Xin-Hui Wang, Yen-Yu Kuo, Chia-Min Yang, Li-Chen Wu, Ja-An Annie Ho","doi":"10.1016/j.jconrel.2025.02.007","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.02.007","url":null,"abstract":"<p><p>Non-muscle invasive bladder cancer (NMIBC) poses significant challenges due to its high recurrence rates and the difficulty in accurately distinguishing tumor lesions. Effective and economical methods for identifying cancerous tissues are urgently needed. In this study, we employed thiolated hollow mesoporous silica nanoparticles loaded with Evans blue (EB@HMSN(E)-SH), a traditional tumor staining dye, in conjunction with white light cystoscopy (WLC) to enhance the detection of bladder tumors. We observed that EB@HMSN(E)-SH exhibited mucoadhesive properties, demonstrating significant aggregation upon interaction with mucin, as assessed by the mucin-particle method using Dynamic Light Scattering (DLS). The permeation-enhancing capability of EB@HMSN(E)-SH was evaluated using tumor spheroid models. Despite repeated flushing, EB@HMSN(E)-SH adhered effectively to the mice bladder mucosa, aiding in the differentiation of tumor tissue from normal and inflammatory lesions, facilitated by the disordered structure of tumor tissue. Tissues stained with EB@HMSN(E)-SH showed co-localization with NBT-2 tumor cells expressing GFP, confirmed by confocal microscopy, which revealed deeper penetration of EB released from HMSN(E)-SH into bladder tumors compared to free EB. The combined use of WLC and EB@HMSN(E)-SH enabled precise identification of tumor-like tissues, corroborated by histopathological examination using H&E staining. The mucoadhesive properties and extended retention time of EB@HMSN(E)-SH complement WLC effectively in identifying NMIBC, suggesting its potential as a promising diagnostic tool.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374179","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}
Pub Date : 2025-02-05DOI: 10.1016/j.jconrel.2025.01.093
Xiaotong Hu , Daping Xie , Yuwei Li , Yiming Niu , Rongwei Tan , Zhending She , Chunming Wang
Artificial dermal matrixes (ADMs) are valuable clinical options for treating large soft tissue defects, but their suboptimal bioactivities compared with the real tissue limit their therapeutic potential. For example, glycosaminoglycan (GAG) polysaccharides in the native skin vitally and differentially regulate endogenous growth factors (GFs) to maintain tissue homeostasis. However, the GAG used in the current ADMs has often lost such delicate regulation. Here, we developed a novel polysaccharide-based ADM that can promote skin tissue repair through selective modulation of specific pro-healing GFs. First, we prepared a plant-derived backbone of glucomannan (named BSP) – representing the two dominant monosaccharide components in the human body – in mass and homogenic quality. Then, we modified this backbone with sulfate and acetyl groups in a controlled manner to yield an optimized BSP derivative (SMAL-BSP) as a main composition to generate a new ADM. In vitro, SMAL-BSP enabled the ADM to selectively sequester pro-angiogenic GFs of VEGF-A and FGF-2 in situ for stimulating endothelial cell growth. Moreover, the addition of the acetyl group induced macrophages to secrete nitric oxide (NO) with antibacterial activities. Further in vivo tests in a rat model of full-thickness skin wounds indicated that SMAL-BSP ADM could sequester GFs in situ to promote angiogenesis and thus tissue regeneration, with superior effects than conventional chondroitin sulfate-based ADM, while showing no adverse effects often associated with animal-derived products. Our study represents a novel strategy for ADM design, targeting selective GF sequestration towards optimal skin tissue regeneration.
{"title":"A dual-modified glucomannan polysaccharide selectively sequesters growth factors for skin tissue repair","authors":"Xiaotong Hu , Daping Xie , Yuwei Li , Yiming Niu , Rongwei Tan , Zhending She , Chunming Wang","doi":"10.1016/j.jconrel.2025.01.093","DOIUrl":"10.1016/j.jconrel.2025.01.093","url":null,"abstract":"<div><div>Artificial dermal matrixes (ADMs) are valuable clinical options for treating large soft tissue defects, but their suboptimal bioactivities compared with the real tissue limit their therapeutic potential. For example, glycosaminoglycan (GAG) polysaccharides in the native skin vitally and differentially regulate endogenous growth factors (GFs) to maintain tissue homeostasis. However, the GAG used in the current ADMs has often lost such delicate regulation. Here, we developed a novel polysaccharide-based ADM that can promote skin tissue repair through selective modulation of specific pro-healing GFs. First, we prepared a plant-derived backbone of glucomannan (named BSP) – representing the two dominant monosaccharide components in the human body – in mass and homogenic quality. Then, we modified this backbone with sulfate and acetyl groups in a controlled manner to yield an optimized BSP derivative (S<sup>M</sup>A<sup>L</sup>-BSP) as a main composition to generate a new ADM. In vitro, S<sup>M</sup>A<sup>L</sup>-BSP enabled the ADM to selectively sequester pro-angiogenic GFs of VEGF-A and FGF-2 in situ for stimulating endothelial cell growth. Moreover, the addition of the acetyl group induced macrophages to secrete nitric oxide (NO) with antibacterial activities. Further in vivo tests in a rat model of full-thickness skin wounds indicated that S<sup>M</sup>A<sup>L</sup>-BSP ADM could sequester GFs in situ to promote angiogenesis and thus tissue regeneration, with superior effects than conventional chondroitin sulfate-based ADM, while showing no adverse effects often associated with animal-derived products. Our study represents a novel strategy for ADM design, targeting selective GF sequestration towards optimal skin tissue regeneration.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 185-198"},"PeriodicalIF":10.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079824","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}
Pub Date : 2025-02-05DOI: 10.1016/j.jconrel.2025.01.063
Mingxia Jiang , Huapan Fang , Huayu Tian
Biomedical polymers are at the forefront of medical advancements, offering innovative solutions in disease prevention, diagnosis, treatment, and clinical use due to their exceptional physicochemical properties. This review delves into the characteristics, classification, and preparation methods of these polymers, highlighting their diverse applications in drug delivery, medical imaging, tissue engineering, and regenerative medicine. We present a thorough analysis of the recent advancements in biomedical polymer research and their clinical applications, acknowledging the challenges that remain, such as immune response management, controlled degradation rates, and mechanical property optimization. Addressing these issues, we explore future directions, including personalization and the integration of nanotechnology, which hold significant potential for further advancing the field. This comprehensive review aims to provide a deep understanding of biomedical polymers and serve as a valuable resource for the development of innovative polymer materials in both fundamental research and clinical practice.
{"title":"Latest advancements and trends in biomedical polymers for disease prevention, diagnosis, treatment, and clinical application","authors":"Mingxia Jiang , Huapan Fang , Huayu Tian","doi":"10.1016/j.jconrel.2025.01.063","DOIUrl":"10.1016/j.jconrel.2025.01.063","url":null,"abstract":"<div><div>Biomedical polymers are at the forefront of medical advancements, offering innovative solutions in disease prevention, diagnosis, treatment, and clinical use due to their exceptional physicochemical properties. This review delves into the characteristics, classification, and preparation methods of these polymers, highlighting their diverse applications in drug delivery, medical imaging, tissue engineering, and regenerative medicine. We present a thorough analysis of the recent advancements in biomedical polymer research and their clinical applications, acknowledging the challenges that remain, such as immune response management, controlled degradation rates, and mechanical property optimization. Addressing these issues, we explore future directions, including personalization and the integration of nanotechnology, which hold significant potential for further advancing the field. This comprehensive review aims to provide a deep understanding of biomedical polymers and serve as a valuable resource for the development of innovative polymer materials in both fundamental research and clinical practice.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 138-174"},"PeriodicalIF":10.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066032","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}
Pub Date : 2025-02-05DOI: 10.1016/j.jconrel.2025.01.079
Jian-Xuan Sun , Qi-Dong Xia , Jin-Zhou Xu , Ye An , Si-Yang Ma , Jing-Yu Xu , Jia-Cheng Xiang , Chen-Qian Liu , Meng-Yao Xu , Si-Han Zhang , Yang Luan , Ke Tang , Shao-Gang Wang
Radical prostatectomy with pelvic lymph node dissection is the best treatment for intermediate- to high-risk localized prostate cancer (PCa). However, conventional white light surgery has difficulties in identifying tumor boundary and micrometastases intraoperatively. Fluorescence guided surgery (FGS) can solve the above difficulties, but lacks tumor-specific near-infrared fluorescent (NIRF) probes in PCa. STEAP1 was an ideal target in PCa treatment and imaging. Here, we constructed a PCa specific fluorescent probe based on extracellular vesicles targeting STEAP1 (AS-EVs) loaded with NIRF dye S0456 and evaluated its preclinical profiles. In vitro and in vivo studies both showed S0456@AS-EVs was safe and showed strong targeting ability to PCa in various mice xenograft models. S0456@AS-EVs could clear rapidly from blood (half-time of 4.29 h) and retain in the STEAP1 positive tumor tissues for more than 72 h with the highest tumor background ratio (TBR) of 3:1, which was superior to ICG, free S0456, ICG@Ctrl-EVs and S0456@Ctrl-EVs (p < 0.01). Finally, S0456@AS-EVs was applied in FGS on intramuscular model, and the tumors were resected under white light and fluorescence respectively. Compared with white light surgery, mice undergoing FGS had lower positive margin rate and better postoperative survival (p = 0.0342).
{"title":"A novel prostate cancer-specific fluorescent probe based on extracellular vesicles targeting STEAP1 applied in fluorescence guided surgery","authors":"Jian-Xuan Sun , Qi-Dong Xia , Jin-Zhou Xu , Ye An , Si-Yang Ma , Jing-Yu Xu , Jia-Cheng Xiang , Chen-Qian Liu , Meng-Yao Xu , Si-Han Zhang , Yang Luan , Ke Tang , Shao-Gang Wang","doi":"10.1016/j.jconrel.2025.01.079","DOIUrl":"10.1016/j.jconrel.2025.01.079","url":null,"abstract":"<div><div>Radical prostatectomy with pelvic lymph node dissection is the best treatment for intermediate- to high-risk localized prostate cancer (PCa). However, conventional white light surgery has difficulties in identifying tumor boundary and micrometastases intraoperatively. Fluorescence guided surgery (FGS) can solve the above difficulties, but lacks tumor-specific near-infrared fluorescent (NIRF) probes in PCa. STEAP1 was an ideal target in PCa treatment and imaging. Here, we constructed a PCa specific fluorescent probe based on extracellular vesicles targeting STEAP1 (AS-EVs) loaded with NIRF dye S0456 and evaluated its preclinical profiles. In vitro and in vivo studies both showed S0456@AS-EVs was safe and showed strong targeting ability to PCa in various mice xenograft models. S0456@AS-EVs could clear rapidly from blood (half-time of 4.29 h) and retain in the STEAP1 positive tumor tissues for more than 72 h with the highest tumor background ratio (TBR) of 3:1, which was superior to ICG, free S0456, ICG@Ctrl-EVs and S0456@Ctrl-EVs (<em>p</em> < 0.01). Finally, S0456@AS-EVs was applied in FGS on intramuscular model, and the tumors were resected under white light and fluorescence respectively. Compared with white light surgery, mice undergoing FGS had lower positive margin rate and better postoperative survival (<em>p</em> = 0.0342).</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 199-218"},"PeriodicalIF":10.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-05DOI: 10.1016/j.jconrel.2025.01.071
Li Zhang , Brandon Yi Loong Seow , Ki Hyun Bae , Yue Zhang , Kuo-Chieh Liao , Yue Wan , Yi Yan Yang
mRNA-loaded lipid nanoparticles (mRNA-LNPs) hold great potential for disease treatment and prevention. LNPs are normally made from four lipids including ionizable lipid, helper lipid, cholesterol, and PEGylated lipid (PEG-lipid). Although PEG-lipid has the lowest content, it plays a crucial role in the effective delivery of mRNA-LNPs. However, previous studies have yet to elucidate the key factors of PEG-lipid that influence the properties of LNPs. This study reported how PEG-lipid content, lipid tail length, and chemical linkage between PEG and lipid affected in vitro and in vivo properties of mRNA-LNPs. Forty-eight LNP formulations were prepared and characterized. The results revealed that a PEG-lipid molar content exceeding 3.0 % significantly reduced the encapsulation efficiency of mRNA in LNPs via manual mixing. An increased PEG-lipid content also significantly decreased mRNA translation efficiency. Although the chemical linkage had minimal impact, the lipid tail length of PEG-lipid significantly affected the properties of mRNA-LNPs, irrespective of whether the LNPs were prepared using manual or microfluidic mixing. mRNA-LNPs made from ALC-0159 with C14 lipid tails, which is used in Pfizer/BioNTech COVID-19 mRNA vaccines, or C16-Ceramide-PEG preferably accumulated in the liver, while mRNA-LNPs prepared from C8-Ceramide-PEG were largely found in the lymph nodes. In a mouse SARS-CoV-2 Delta variant spike protein-encoded mRNA vaccine model, mRNA-LNPs made from either C8-Ceramide-PEG or C16-Ceramide-PEG yielded comparable vaccination efficacy to mRNA-LNPs made from ALC-0159, while mRNA-LNPs formulated with DSPE-PEG with C18 lipid tails mediated lower vaccination efficacy. C16-Ceramide-PEG LNPs and DSPE-PEG LNPs induced higher anti-PEG antibody response than C8-Ceramide-PEG and ALC-0159 LNPs. All the LNPs tested did not cause significant toxicity in mice. These results offer valuable insights into the use of PEG-lipid in LNP formulations and suggest that C8-Ceramide-PEG holds potential for use in the formulation of mRNA vaccine-loaded LNPs.
{"title":"Role of PEGylated lipid in lipid nanoparticle formulation for in vitro and in vivo delivery of mRNA vaccines","authors":"Li Zhang , Brandon Yi Loong Seow , Ki Hyun Bae , Yue Zhang , Kuo-Chieh Liao , Yue Wan , Yi Yan Yang","doi":"10.1016/j.jconrel.2025.01.071","DOIUrl":"10.1016/j.jconrel.2025.01.071","url":null,"abstract":"<div><div>mRNA-loaded lipid nanoparticles (mRNA-LNPs) hold great potential for disease treatment and prevention. LNPs are normally made from four lipids including ionizable lipid, helper lipid, cholesterol, and PEGylated lipid (PEG-lipid). Although PEG-lipid has the lowest content, it plays a crucial role in the effective delivery of mRNA-LNPs. However, previous studies have yet to elucidate the key factors of PEG-lipid that influence the properties of LNPs. This study reported how PEG-lipid content, lipid tail length, and chemical linkage between PEG and lipid affected <em>in vitro</em> and <em>in vivo</em> properties of mRNA-LNPs. Forty-eight LNP formulations were prepared and characterized. The results revealed that a PEG-lipid molar content exceeding 3.0 % significantly reduced the encapsulation efficiency of mRNA in LNPs <em>via</em> manual mixing. An increased PEG-lipid content also significantly decreased mRNA translation efficiency. Although the chemical linkage had minimal impact, the lipid tail length of PEG-lipid significantly affected the properties of mRNA-LNPs, irrespective of whether the LNPs were prepared using manual or microfluidic mixing. mRNA-LNPs made from ALC-0159 with C14 lipid tails, which is used in Pfizer/BioNTech COVID-19 mRNA vaccines, or C16-Ceramide-PEG preferably accumulated in the liver, while mRNA-LNPs prepared from C8-Ceramide-PEG were largely found in the lymph nodes. In a mouse SARS-CoV-2 Delta variant spike protein-encoded mRNA vaccine model, mRNA-LNPs made from either C8-Ceramide-PEG or C16-Ceramide-PEG yielded comparable vaccination efficacy to mRNA-LNPs made from ALC-0159, while mRNA-LNPs formulated with DSPE-PEG with C18 lipid tails mediated lower vaccination efficacy. C16-Ceramide-PEG LNPs and DSPE-PEG LNPs induced higher anti-PEG antibody response than C8-Ceramide-PEG and ALC-0159 LNPs. All the LNPs tested did not cause significant toxicity in mice. These results offer valuable insights into the use of PEG-lipid in LNP formulations and suggest that C8-Ceramide-PEG holds potential for use in the formulation of mRNA vaccine-loaded LNPs.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 108-124"},"PeriodicalIF":10.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056825","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}
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