Pub Date : 2026-02-05DOI: 10.1016/j.jconrel.2026.114688
Jiamin Li, Rongrong Li, Yan Zhou, Shengping Zheng, Jingjing Xu, Jingli Zhu, Yunqing Pang, Jing Wang
The treatment of diabetic periodontitis is significantly challenged by a pathological microenvironment characterized by hyperglycemia, proinflammatory cytokine storm, and excessive reactive oxygen species (ROS), with current therapeutic strategies offering limited efficacy and susceptibility to antibiotic resistance. Although liraglutide (LIRA) possesses multifaceted therapeutic potential, including glycemic control, anti-inflammation, antioxidation, and osteoprotection, its systemic administration fails to achieve effective local concentrations within periodontal tissues. To address this, we engineered an injectable carboxymethyl chitosan-oxidized dextran hydrogel (LIRA@CMCS-OD) via dynamic Schiff base bonds for localized LIRA delivery. This hydrogel exhibited excellent injectability, tissue adhesion, biocompatibility, and pH-responsive drug release kinetics. In vitro studies demonstrated that LIRA@CMCS-OD inhibited Porphyromonas gingivalis growth, effectively scavenged intracellular ROS in human periodontal ligament cells (hPDLCs), and robustly promoted hPDLCs osteogenic differentiation. In a diabetic periodontitis rat model, local application of LIRA@CMCS-OD significantly ameliorated gingival inflammation and tooth mobility, enhanced alveolar bone regeneration, and demonstrated favorable biosafety. By enabling sustained local drug release and orchestrating a synergistic “antibacterial action-antioxidation- osteogenic protection” mechanism, this LIRA-loaded injectable hydrogel presents a potent and safe therapeutic strategy for diabetic periodontitis.
{"title":"Injectable Schiff base-engineered hydrogel for spatiotemporal liraglutide delivery orchestrates diabetic periodontitis regression via multimodal microenvironment reprogramming","authors":"Jiamin Li, Rongrong Li, Yan Zhou, Shengping Zheng, Jingjing Xu, Jingli Zhu, Yunqing Pang, Jing Wang","doi":"10.1016/j.jconrel.2026.114688","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114688","url":null,"abstract":"The treatment of diabetic periodontitis is significantly challenged by a pathological microenvironment characterized by hyperglycemia, proinflammatory cytokine storm, and excessive reactive oxygen species (ROS), with current therapeutic strategies offering limited efficacy and susceptibility to antibiotic resistance. Although liraglutide (LIRA) possesses multifaceted therapeutic potential, including glycemic control, anti-inflammation, antioxidation, and osteoprotection, its systemic administration fails to achieve effective local concentrations within periodontal tissues. To address this, we engineered an injectable carboxymethyl chitosan-oxidized dextran hydrogel (LIRA@CMCS-OD) via dynamic Schiff base bonds for localized LIRA delivery. This hydrogel exhibited excellent injectability, tissue adhesion, biocompatibility, and pH-responsive drug release kinetics. In vitro studies demonstrated that LIRA@CMCS-OD inhibited <em>Porphyromonas gingivalis</em> growth, effectively scavenged intracellular ROS in human periodontal ligament cells (hPDLCs), and robustly promoted hPDLCs osteogenic differentiation. In a diabetic periodontitis rat model, local application of LIRA@CMCS-OD significantly ameliorated gingival inflammation and tooth mobility, enhanced alveolar bone regeneration, and demonstrated favorable biosafety. By enabling sustained local drug release and orchestrating a synergistic “antibacterial action-antioxidation- osteogenic protection” mechanism, this LIRA-loaded injectable hydrogel presents a potent and safe therapeutic strategy for diabetic periodontitis.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"17 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122107","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 : 2026-02-04DOI: 10.1016/j.jconrel.2026.114673
Jingjuan Zhang , Yongzheng Li , Huiyuan Jin , Peizhen Yang , Huan Min , Jian Song , Yingqiu Qi
Proteolysis targeting chimeras (PROTACs) are catalytic degraders that eliminate pathogenic proteins via the ubiquitin-proteasome system (UPS). Building on this mechanism, nano-engineered PROTACs (Nano-PROTACs) integrate PROTACs with rationally designed nanomaterials to create an emerging therapeutic platform for cancer. This integrative approach preserves the core capability of PROTACs to precisely degrade pathogenic proteins through the UPS, and also confers multiple therapeutic advantages including enhanced tissue targeting, improved membrane permeability, and controlled drug release, thereby significantly improving cancer therapeutic efficacy while effectively reducing systemic toxicity. This review provides a comprehensive overview of recent advances in Nano-PROTACs for cancer therapy, with a particular focus on the design strategies enabled by nanomaterial-based delivery systems, along with the applications in monotherapy and synergistic therapies. In addition, the therapeutic advantages and existing challenges of Nano-PROTACs are critically discussed, while delineating their potential future clinical applications, providing critical insights to the understanding of this emerging technology and offering novel perspectives for future development of precision therapeutics.
{"title":"New-generation advanced Nano-PROTACs as potential therapeutic agents in cancer therapy","authors":"Jingjuan Zhang , Yongzheng Li , Huiyuan Jin , Peizhen Yang , Huan Min , Jian Song , Yingqiu Qi","doi":"10.1016/j.jconrel.2026.114673","DOIUrl":"10.1016/j.jconrel.2026.114673","url":null,"abstract":"<div><div>Proteolysis targeting chimeras (PROTACs) are catalytic degraders that eliminate pathogenic proteins via the ubiquitin-proteasome system (UPS). Building on this mechanism, nano-engineered PROTACs (Nano-PROTACs) integrate PROTACs with rationally designed nanomaterials to create an emerging therapeutic platform for cancer. This integrative approach preserves the core capability of PROTACs to precisely degrade pathogenic proteins through the UPS, and also confers multiple therapeutic advantages including enhanced tissue targeting, improved membrane permeability, and controlled drug release, thereby significantly improving cancer therapeutic efficacy while effectively reducing systemic toxicity. This review provides a comprehensive overview of recent advances in Nano-PROTACs for cancer therapy, with a particular focus on the design strategies enabled by nanomaterial-based delivery systems, along with the applications in monotherapy and synergistic therapies. In addition, the therapeutic advantages and existing challenges of Nano-PROTACs are critically discussed, while delineating their potential future clinical applications, providing critical insights to the understanding of this emerging technology and offering novel perspectives for future development of precision therapeutics.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114673"},"PeriodicalIF":11.5,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122130","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 : 2026-02-04DOI: 10.1016/j.jconrel.2026.114687
Xin Huang , Yan-Yun Sun , Yi-Ren Qin , Hong Chen , Ting-Ting Pan , Song-Song Zhao , Qian Cai , Xiao-Shuo Zhang , Xiao-Dong Nie , Lei Feng , Hua Hu , Yong Tang , Pei-Zhuo Zhang , Zhi-Yuan Zhong , Jie Li , Li Lu , Feng-Hua Meng , Quan-Hong Ma
Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD.
{"title":"ApoE-directed CpG nano-immunoadjuvant ameliorates Alzheimer's-like pathology in mice","authors":"Xin Huang , Yan-Yun Sun , Yi-Ren Qin , Hong Chen , Ting-Ting Pan , Song-Song Zhao , Qian Cai , Xiao-Shuo Zhang , Xiao-Dong Nie , Lei Feng , Hua Hu , Yong Tang , Pei-Zhuo Zhang , Zhi-Yuan Zhong , Jie Li , Li Lu , Feng-Hua Meng , Quan-Hong Ma","doi":"10.1016/j.jconrel.2026.114687","DOIUrl":"10.1016/j.jconrel.2026.114687","url":null,"abstract":"<div><div>Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114687"},"PeriodicalIF":11.5,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131979","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 : 2026-02-03DOI: 10.1016/j.jconrel.2026.114684
Jinwei Zhu , Hui Lin , Kejie Wang , Sasa Zhang , Hua He , Kun Hao
The long-held assumption that passive diffusion governs nanomedicine entry into the tumors has been increasingly challenged, with accumulating evidence implicating transcytosis as an important route for nanoparticle transport across the tumor endothelium. However, quantitative comparisons of their relative contributions remain scarce. To address this gap, this study developed a minimal physiologically based pharmacokinetic (m-PBPK) model that integrates in vitro cellular kinetic data to quantitatively describe to tumor delivery of nanoparticles and to assess the relative contributions of diffusion- and transcytosis-mediated transport within a model-based context. The framework was evaluated using PEGylated gold nanoparticles (AuNPs) spanning a range of particle sizes and incorporated empirical size-parameter relationships to enable in vitro-in vivo translational analysis. Model simulations suggested that transcytosis-mediated processes account for the majority of tumor AuNP accumulation under the modeled physiological conditions (99.0 %, 95 % CI: 94.7 %–99.8 %), whereas passive diffusion contributed a smaller fraction under most conditions examined. Dose-dependent analysis further indicated a capacity-limited tumor accumulation behavior, with a threshold around 18 mg, beyond which increasing the dose to 100 mg resulted in only a modest (∼15 %) increase in tumor accumulation. Sensitivity analyses indicated that systemic exposure and endothelial intracellular trafficking behavior are key determinants influencing tumor delivery, whereas enhanced intracellular sequestration consistently reduced tumor accumulation across dose levels. Overall, the proposed m-PBPK framework provides mechanistically interpretable, proof-of-concept insights into nanoparticle tumor delivery, supporting quantitative assessment of transcytosis efficiency and dose-dependent accumulation behavior for hypothesis generation in nanomedicine development.
{"title":"Translational m-PBPK Modeling reveals active transcytosis as the pivotal mechanism for nanoparticle tumor delivery: Implications for dose optimization","authors":"Jinwei Zhu , Hui Lin , Kejie Wang , Sasa Zhang , Hua He , Kun Hao","doi":"10.1016/j.jconrel.2026.114684","DOIUrl":"10.1016/j.jconrel.2026.114684","url":null,"abstract":"<div><div>The long-held assumption that passive diffusion governs nanomedicine entry into the tumors has been increasingly challenged, with accumulating evidence implicating transcytosis as an important route for nanoparticle transport across the tumor endothelium. However, quantitative comparisons of their relative contributions remain scarce. To address this gap, this study developed a minimal physiologically based pharmacokinetic (m-PBPK) model that integrates in vitro cellular kinetic data to quantitatively describe to tumor delivery of nanoparticles and to assess the relative contributions of diffusion- and transcytosis-mediated transport within a model-based context. The framework was evaluated using PEGylated gold nanoparticles (AuNPs) spanning a range of particle sizes and incorporated empirical size-parameter relationships to enable in vitro<em>-</em>in vivo translational analysis. Model simulations suggested that transcytosis-mediated processes account for the majority of tumor AuNP accumulation under the modeled physiological conditions (99.0 %, 95 % CI: 94.7 %–99.8 %), whereas passive diffusion contributed a smaller fraction under most conditions examined. Dose-dependent analysis further indicated a capacity-limited tumor accumulation behavior, with a threshold around 18 mg, beyond which increasing the dose to 100 mg resulted in only a modest (∼15 %) increase in tumor accumulation. Sensitivity analyses indicated that systemic exposure and endothelial intracellular trafficking behavior are key determinants influencing tumor delivery, whereas enhanced intracellular sequestration consistently reduced tumor accumulation across dose levels. Overall, the proposed m-PBPK framework provides mechanistically interpretable, proof-of-concept insights into nanoparticle tumor delivery, supporting quantitative assessment of transcytosis efficiency and dose-dependent accumulation behavior for hypothesis generation in nanomedicine development.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114684"},"PeriodicalIF":11.5,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109924","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 : 2026-02-03DOI: 10.1016/j.jconrel.2026.114674
Teertha Ayanji , Na Yan , Litian Jia , Ke Cheng
Exosomes, as naturally derived extracellular vesicles, have emerged as promising therapeutic carriers due to their intrinsic biocompatibility, low immunogenicity, and ability to facilitate intercellular communication. In recent years, the non-invasive administration of exosomes has gained increasing attention as a strategy to enhance patient compliance and improve drug delivery efficiency while circumventing the limitations associated with traditional invasive routes. This review provides a comprehensive overview of the non-invasive delivery of exosome-based therapeutics, spanning oral, intranasal, inhalation, ocular, and transdermal administration. Moreover, we discuss underexplored pathways with unique anatomical and physiological advantages for systemic and local therapy, including sublingual, otic, rectal, and vaginal delivery. Each administration route will outline the key anatomic and biological barriers that exosomes must overcome, along with commonly employed strategies to address them. We further explore the therapeutic potential of non-invasive exosome delivery across various diseases, highlighting the advantages and limitations of each approach. Finally, we discuss the current challenges in translating non-invasive exosome delivery into clinical practice and propose future directions to advance this goal.
{"title":"Non-invasive administration of exosomes","authors":"Teertha Ayanji , Na Yan , Litian Jia , Ke Cheng","doi":"10.1016/j.jconrel.2026.114674","DOIUrl":"10.1016/j.jconrel.2026.114674","url":null,"abstract":"<div><div>Exosomes, as naturally derived extracellular vesicles, have emerged as promising therapeutic carriers due to their intrinsic biocompatibility, low immunogenicity, and ability to facilitate intercellular communication. In recent years, the non-invasive administration of exosomes has gained increasing attention as a strategy to enhance patient compliance and improve drug delivery efficiency while circumventing the limitations associated with traditional invasive routes. This review provides a comprehensive overview of the non-invasive delivery of exosome-based therapeutics, spanning oral, intranasal, inhalation, ocular, and transdermal administration. Moreover, we discuss underexplored pathways with unique anatomical and physiological advantages for systemic and local therapy, including sublingual, otic, rectal, and vaginal delivery. Each administration route will outline the key anatomic and biological barriers that exosomes must overcome, along with commonly employed strategies to address them. We further explore the therapeutic potential of non-invasive exosome delivery across various diseases, highlighting the advantages and limitations of each approach. Finally, we discuss the current challenges in translating non-invasive exosome delivery into clinical practice and propose future directions to advance this goal.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114674"},"PeriodicalIF":11.5,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109922","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}
Acetaminophen (APAP) overdose-induced liver damage is a serious clinical issue primarily caused by mitochondrial dysfunction in hepatocytes. Coenzyme Q10 (CoQ10) exhibits mitochondrial protective effects and is considered a promising therapeutic candidate. However, it has difficulty targeting liver mitochondria because of its high hydrophobicity and low bioavailability. To address the therapeutic limitations of CoQ10 caused by poor mitochondrial bioavailability, this study aimed to establish a rational design to systematically evaluate how particle size and lipid composition influence the therapeutic efficacy of CoQ10-loaded nanocarriers on APAP-induced liver injury (AILI). Three types of CoQ10-loaded mitochondrial-targeted nanocarriers (CoQ10-MITO-Porter) of different particle sizes (50, 100, 200 nm) and CoQ10-LP, which mimics liposomes used in clinical applications, were prepared using a microfluidic device. These nanocarriers were administered to AILI model mice at early stages of disease, and their hepatic and mitochondrial accumulation, therapeutic impact on serum biomarkers, histological damage, and CoQ10 delivery efficiency were evaluated systematically. The 50-nm CoQ10-MITO-Porter showed the highest hepatoprotective efficacy, indicated by marked attenuation of serum alanine aminotransferase levels and reduced hepatic necrosis. The effect decreased with increasing particle size and was minimal for CoQ10-LP. These results highlight the importance of systematic evaluation of nanocarrier physicochemical properties to achieve effective mitochondrial delivery of CoQ10 in early-phase AILI. These findings are expected to serve as a foundation for the development of mitochondria-targeted nanomedicines that alleviate early-phase hepatic damage and may extend to other mitochondrial-related diseases.
{"title":"Mitochondria-targeted coenzyme Q10 nanocarriers evaluated by particle size and lipid composition alleviate early acetaminophen-induced liver injury","authors":"Mitsue Hibino, Yukari Muramatsu, Hideyoshi Harashima, Yuma Yamada","doi":"10.1016/j.jconrel.2026.114682","DOIUrl":"10.1016/j.jconrel.2026.114682","url":null,"abstract":"<div><div>Acetaminophen (APAP) overdose-induced liver damage is a serious clinical issue primarily caused by mitochondrial dysfunction in hepatocytes. Coenzyme Q<sub>10</sub> (CoQ<sub>10</sub>) exhibits mitochondrial protective effects and is considered a promising therapeutic candidate. However, it has difficulty targeting liver mitochondria because of its high hydrophobicity and low bioavailability. To address the therapeutic limitations of CoQ<sub>10</sub> caused by poor mitochondrial bioavailability, this study aimed to establish a rational design to systematically evaluate how particle size and lipid composition influence the therapeutic efficacy of CoQ<sub>10</sub>-loaded nanocarriers on APAP-induced liver injury (AILI). Three types of CoQ<sub>10</sub>-loaded mitochondrial-targeted nanocarriers (CoQ<sub>10</sub>-MITO-Porter) of different particle sizes (50, 100, 200 nm) and CoQ<sub>10</sub>-LP, which mimics liposomes used in clinical applications, were prepared using a microfluidic device. These nanocarriers were administered to AILI model mice at early stages of disease, and their hepatic and mitochondrial accumulation, therapeutic impact on serum biomarkers, histological damage, and CoQ<sub>10</sub> delivery efficiency were evaluated systematically. The 50-nm CoQ<sub>10</sub>-MITO-Porter showed the highest hepatoprotective efficacy, indicated by marked attenuation of serum alanine aminotransferase levels and reduced hepatic necrosis. The effect decreased with increasing particle size and was minimal for CoQ<sub>10</sub>-LP. These results highlight the importance of systematic evaluation of nanocarrier physicochemical properties to achieve effective mitochondrial delivery of CoQ<sub>10</sub> in early-phase AILI. These findings are expected to serve as a foundation for the development of mitochondria-targeted nanomedicines that alleviate early-phase hepatic damage and may extend to other mitochondrial-related diseases.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114682"},"PeriodicalIF":11.5,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109921","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 : 2026-02-02DOI: 10.1016/j.jconrel.2026.114680
Xiaolan Xu , Jiahao An , Dan Bai , Yuanchao Xu , Tingting Wu , Hua Yang , Yueyue Yan , Shaojun Yang , Zifan Wei , Yuchen Yao , Qian Liu , Tao Xu , Lan Zhu
Efficient delivery of messenger RNA (mRNA) to dendritic cells (DCs) remains a major challenge limiting the efficacy of mRNA cancer vaccines. Here, we report a large-sized lipid nanoparticle (LLNP) platform specifically engineered for enhanced DC targeting. By reducing PEG–lipid content to 0.3% and proportionally increasing the concentrations of structural lipids and mRNA sixfold relative to the Moderna classic formulation, we generated LLNPs with enlarged size and optimized surface properties that favor DC uptake. Following intravenous administration, LLNPs achieved markedly enhanced mRNA expression in DCs, with ∼82% of GFP+ cells identified as DCs and ∼ 44% of CD11c+ DCs expressing GFP. LLNPs also promoted DC maturation and antigen presentation. LLNP-mediated delivery of HPV16 E6E7 mRNA elicited robust effector and memory cytotoxic T lymphocyte responses, enabling effective tumor regression at doses as low as 1 μg. Both conventional type 1 dendritic cells (cDC1) and conventional type 2 dendritic cells contributed to antigen presentation, with cDC1 playing the predominant role. Compared with BioNTech's RNA–lipoplex delivery platform, LLNPs demonstrated superior DC transfection, T cell activation, and antitumor efficacy. Collectively, these findings establish LLNPs as a robust and versatile platform for next-generation mRNA cancer vaccines with enhanced therapeutic potential.
{"title":"Large and low-PEG lipid nanoparticles enable efficient dendritic cell targeting for potent mRNA Cancer vaccines","authors":"Xiaolan Xu , Jiahao An , Dan Bai , Yuanchao Xu , Tingting Wu , Hua Yang , Yueyue Yan , Shaojun Yang , Zifan Wei , Yuchen Yao , Qian Liu , Tao Xu , Lan Zhu","doi":"10.1016/j.jconrel.2026.114680","DOIUrl":"10.1016/j.jconrel.2026.114680","url":null,"abstract":"<div><div>Efficient delivery of messenger RNA (mRNA) to dendritic cells (DCs) remains a major challenge limiting the efficacy of mRNA cancer vaccines. Here, we report a large-sized lipid nanoparticle (LLNP) platform specifically engineered for enhanced DC targeting. By reducing PEG–lipid content to 0.3% and proportionally increasing the concentrations of structural lipids and mRNA sixfold relative to the Moderna classic formulation, we generated LLNPs with enlarged size and optimized surface properties that favor DC uptake. Following intravenous administration, LLNPs achieved markedly enhanced mRNA expression in DCs, with ∼82% of GFP<sup>+</sup> cells identified as DCs and ∼ 44% of CD11c<sup>+</sup> DCs expressing GFP. LLNPs also promoted DC maturation and antigen presentation. LLNP-mediated delivery of HPV16 E6E7 mRNA elicited robust effector and memory cytotoxic T lymphocyte responses, enabling effective tumor regression at doses as low as 1 μg. Both conventional type 1 dendritic cells (cDC1) and conventional type 2 dendritic cells contributed to antigen presentation, with cDC1 playing the predominant role. Compared with BioNTech's RNA–lipoplex delivery platform, LLNPs demonstrated superior DC transfection, T cell activation, and antitumor efficacy. Collectively, these findings establish LLNPs as a robust and versatile platform for next-generation mRNA cancer vaccines with enhanced therapeutic potential.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114680"},"PeriodicalIF":11.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098412","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 : 2026-02-02DOI: 10.1016/j.jconrel.2026.114679
Anastasiia S. Obozina , Anna M. Iureva , Alexandr A. Kotov , Sergey M. Deyev , Egor S. Korenkov , Victoria O. Shipunova
Targeted therapy is a revolutionary approach in cancer treatment, enabling the precise elimination of malignant cells with fewer side effects than conventional chemotherapy. Among clinically approved strategies, antibody-drug conjugates (ADCs) and immunotoxins represent a rapidly expanding class of biotherapeutics, often serving as theranostic tools when linked to diagnostic components. However, their production requires complex chemical conjugation, making it a technically and economically demanding process. Similarly, nanoparticle-based systems offer targeted delivery but usually rely on multi-step, poorly reproducible syntheses. Here, we introduce a novel type of genetically encoded self-assembling protein nanoparticles with targeting functionality. These nanometer-sized particles, which we propose to term “avisomes”, self-assemble upon refolding of a fusion protein comprising the HER2-specific affibody ZHER2:342 and streptavidin (ZHER2:342-Strp), combining the strengths of bioconjugates and nanoparticles while avoiding the drawbacks of chemical synthesis. Importantly, they are easily and reproducibly synthesized in E. coli. HER2 recognition was confirmed by flow cytometry and fluorescence microscopy. To confer cytotoxic activity, avisomes were loaded with doxorubicin (DOX), yielding ZHER2:342-Strp-DOX nanoparticles that selectively killed HER2-overexpressing cells in vitro. In vivo, treatment with ZHER2:342-Strp-DOX significantly suppressed the growth of HER2-positive tumors in BALB/c mice. Notably, therapy was well tolerated, with no abnormal hematological or biochemical changes, and it alleviated DOX-induced neutropenia. These findings establish avisomes as a highly promising theranostic platform for HER2-positive breast cancer. Its genetically encoded, self-assembling nature eliminates the major limitations of ADCs and synthetic nanoparticles, providing a scalable, reproducible, and cost-efficient alternative for next-generation targeted cancer therapy.
{"title":"Genetically encoded self-assembling affibody-streptavidin nanoparticles for HER2-positive cancer theranostics","authors":"Anastasiia S. Obozina , Anna M. Iureva , Alexandr A. Kotov , Sergey M. Deyev , Egor S. Korenkov , Victoria O. Shipunova","doi":"10.1016/j.jconrel.2026.114679","DOIUrl":"10.1016/j.jconrel.2026.114679","url":null,"abstract":"<div><div>Targeted therapy is a revolutionary approach in cancer treatment, enabling the precise elimination of malignant cells with fewer side effects than conventional chemotherapy. Among clinically approved strategies, antibody-drug conjugates (ADCs) and immunotoxins represent a rapidly expanding class of biotherapeutics, often serving as theranostic tools when linked to diagnostic components. However, their production requires complex chemical conjugation, making it a technically and economically demanding process. Similarly, nanoparticle-based systems offer targeted delivery but usually rely on multi-step, poorly reproducible syntheses. Here, we introduce a novel type of genetically encoded self-assembling protein nanoparticles with targeting functionality. These nanometer-sized particles, which we propose to term “<strong>avisomes</strong>”, self-assemble upon refolding of a fusion protein comprising the HER2-specific affibody Z<sub>HER2:342</sub> and streptavidin (Z<sub>HER2:342</sub>-Strp), combining the strengths of bioconjugates and nanoparticles while avoiding the drawbacks of chemical synthesis. Importantly, they are easily and reproducibly synthesized in <em>E. coli</em>. HER2 recognition was confirmed by flow cytometry and fluorescence microscopy. To confer cytotoxic activity, avisomes were loaded with doxorubicin (DOX), yielding Z<sub>HER2:342</sub>-Strp-DOX nanoparticles that selectively killed HER2-overexpressing cells <em>in vitro</em>. <em>In vivo</em>, treatment with Z<sub>HER2:342</sub>-Strp-DOX significantly suppressed the growth of HER2-positive tumors in BALB/c mice. Notably, therapy was well tolerated, with no abnormal hematological or biochemical changes, and it alleviated DOX-induced neutropenia. These findings establish avisomes as a highly promising theranostic platform for HER2-positive breast cancer. Its genetically encoded, self-assembling nature eliminates the major limitations of ADCs and synthetic nanoparticles, providing a scalable, reproducible, and cost-efficient alternative for next-generation targeted cancer therapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114679"},"PeriodicalIF":11.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109923","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 : 2026-01-31DOI: 10.1016/j.jconrel.2026.114663
Marianne Ashford , Annette Bak
The therapeutic landscape has diversified beyond traditional small molecules to encompass a plethora of different modalities including antibodies, peptides and nucleic acids as well as more complex small molecules. Increasingly heterofunctional molecules, targeted drug conjugates, including antibody drug conjugates, oligonucleotide drug conjugates and radionuclide conjugates, are being used to improve efficacy, reduce side effects and enable lower doses. These diverse modalities present distinct delivery needs. This perspective briefly reflects on the main drug modality classes, their delivery challenges and summarises the current delivery solutions and trends including amorphous solid dispersions, long acting injectables, approaches to high concentration subcutaneous delivery of biologics and lipid nanoparticles for delivery of mRNA. There is a continual drive for more patient centric formulations. We argue that this modality evolution heightens the importance of drug delivery as a core design parameter in discovery rather than as a downstream fix. Across modalities, targeted delivery remains pivotal to improve therapeutic index and to lower dose and environmental footprint. Translational success requires early collaboration among preclinical safety, CMC, clinical, and regulatory teams to define critical quality attributes and develop in vitro/in silico tools for predicting in vivo performance. Delivery science is positioned to play a leading role in enabling the next generation of medicines, accelerating translation, and improving patient outcomes.
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Pub Date : 2026-01-30DOI: 10.1016/j.jconrel.2026.114669
Dingfu Wang , Dan Li , Xiaolin Liu , Shixin Wang , Yile Fan , Ling Lu , Chuanbin Shen , Chunxia Li
Thrombosis remains a leading cause of cardiovascular and cerebrovascular mortality worldwide. Plasminogen activators, notably urokinase and alteplase, have been established as standard thrombolytic agents in clinical practice. However, their therapeutic potential is severely compromised by rapid metabolic clearance, non-specific biodistribution, and associated hemorrhagic complications. Here, we designed a dual-functional nano drug delivery platform that leverages P-selectin overexpression on activated platelets and the characteristic hypoxic microenvironment at thrombotic sites for precision thrombolytic intervention. Specifically, we developed a hypoxia-responsive block (PAC) by conjugating polyguluronate sulfate (PGS, P-selectin targeting motif) with azobenzene-modified cholesterol, enabling urokinase encapsulation within PAC@UK liposomes. Under hypoxic conditions that mimic the thrombotic microenvironment, the reductive cleavage of azobenzene moieties initiated sustained urokinase release (96.41% cumulative release), while maintaining exceptional biocompatibility and demonstrating preferential targeting of activated platelets. Comprehensive in vivo validation across zebrafish, murine mesenteric, and carotid artery thrombosis models revealed markedly enhanced thrombolytic efficacy compared to free UK. This biomimetic nanoplatform represents a paradigm shift toward intelligent, site-specific thrombolytic intervention, offering substantial clinical promise for safer and more effective treatment of thrombotic disorders.
血栓形成仍然是全世界心脑血管死亡的主要原因。纤溶酶原激活剂，特别是尿激酶和阿替普酶，在临床实践中已被确立为标准的溶栓药物。然而，它们的治疗潜力受到快速代谢清除、非特异性生物分布和相关出血并发症的严重损害。在这里，我们设计了一个双重功能的纳米药物递送平台，利用活化血小板上p选择素的过表达和血栓形成部位特有的缺氧微环境来进行精确的溶栓干预。具体来说，我们通过将聚古脲酸盐（PGS， p -选择素靶向基序）与偶氮苯修饰的胆固醇偶联开发了一种缺氧反应阻滞（PAC），使尿激酶包封在PAC@UK脂质体中。在模拟血栓形成微环境的缺氧条件下，偶氮苯部分的还原裂解启动了持续的尿激酶释放（96.41%的累积释放），同时保持了卓越的生物相容性，并显示出对活化血小板的优先靶向性。在斑马鱼、小鼠肠系膜和颈动脉血栓形成模型中进行的全面体内验证显示，与游离UK相比，溶栓效果显著增强。这种仿生纳米平台代表了向智能、位点特异性溶栓干预的范式转变，为更安全、更有效地治疗血栓性疾病提供了实质性的临床前景。
{"title":"Smart hypoxia-responsive sulfated polysaccharides liposomes for controlled and targeted urokinase delivery in thrombotic therapy","authors":"Dingfu Wang , Dan Li , Xiaolin Liu , Shixin Wang , Yile Fan , Ling Lu , Chuanbin Shen , Chunxia Li","doi":"10.1016/j.jconrel.2026.114669","DOIUrl":"10.1016/j.jconrel.2026.114669","url":null,"abstract":"<div><div>Thrombosis remains a leading cause of cardiovascular and cerebrovascular mortality worldwide. Plasminogen activators, notably urokinase and alteplase, have been established as standard thrombolytic agents in clinical practice. However, their therapeutic potential is severely compromised by rapid metabolic clearance, non-specific biodistribution, and associated hemorrhagic complications. Here, we designed a dual-functional nano drug delivery platform that leverages P-selectin overexpression on activated platelets and the characteristic hypoxic microenvironment at thrombotic sites for precision thrombolytic intervention. Specifically, we developed a hypoxia-responsive block (PAC) by conjugating polyguluronate sulfate (PGS, P-selectin targeting motif) with azobenzene-modified cholesterol, enabling urokinase encapsulation within PAC@UK liposomes. Under hypoxic conditions that mimic the thrombotic microenvironment, the reductive cleavage of azobenzene moieties initiated sustained urokinase release (96.41% cumulative release), while maintaining exceptional biocompatibility and demonstrating preferential targeting of activated platelets. Comprehensive <em>in vivo</em> validation across zebrafish, murine mesenteric, and carotid artery thrombosis models revealed markedly enhanced thrombolytic efficacy compared to free UK. This biomimetic nanoplatform represents a paradigm shift toward intelligent, site-specific thrombolytic intervention, offering substantial clinical promise for safer and more effective treatment of thrombotic disorders.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114669"},"PeriodicalIF":11.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089553","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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