Glioblastoma (GBM) remains one of the most intractable malignancies owing to the dual challenges of the blood brain barrier (BBB) and profound immunosuppression. Here, we present a nanobomb (OMV-ApoE@ALF) that integrates heterologous production of the aromatic polyketide albofungin (ALF) with programmable outer membrane vesicles (OMVs) displaying ApoE peptides for GBM immunotherapy. OMV-ApoE@ALF efficiently crossed the BBB, accumulated in tumors, and functioned as a lysosomal nanobomb to boost pyroptosis and activate cGAS-STING pathway, thereby promoting dendritic cell maturation, T-cell infiltration, and durable antitumor immunity. Mechanistically, OMV-ApoE@ALF delivered ALF into lysosomes, inducing lysosomal disruption, reactive oxygen species (ROS) production, and subsequent mitochondrial damage. Crucially, this lysosomal rupture also suppressed protective autophagy of tumor cells themselves, thereby reinforcing the cascade activation between caspase-3/GSDME-dependent pyroptosis and cGAS-STING signaling pathway. This lysosomal disruption-nanobomb represents a new strategy for advancing GBM immunotherapy.
{"title":"Albofungin vesicle nanobombs trigger lysosomal disruption for self-enhanced pyroptosis and cGAS-STING pathway activation in glioblastoma immunotherapy","authors":"Chen Chen, Shuai Tan, Xiaojing Zhu, Zefeng Song, Yutong Xing, Wenrui Jin, Jingyi Xu, Siqi Song, Haoran Geng, Xingyu Chen, Chunshuai Huang, Zhenyong Wu","doi":"10.1016/j.jconrel.2026.114718","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114718","url":null,"abstract":"Glioblastoma (GBM) remains one of the most intractable malignancies owing to the dual challenges of the blood brain barrier (BBB) and profound immunosuppression. Here, we present a nanobomb (OMV-ApoE@ALF) that integrates heterologous production of the aromatic polyketide albofungin (ALF) with programmable outer membrane vesicles (OMVs) displaying ApoE peptides for GBM immunotherapy. OMV-ApoE@ALF efficiently crossed the BBB, accumulated in tumors, and functioned as a lysosomal nanobomb to boost pyroptosis and activate cGAS-STING pathway, thereby promoting dendritic cell maturation, T-cell infiltration, and durable antitumor immunity. Mechanistically, OMV-ApoE@ALF delivered ALF into lysosomes, inducing lysosomal disruption, reactive oxygen species (ROS) production, and subsequent mitochondrial damage. Crucially, this lysosomal rupture also suppressed protective autophagy of tumor cells themselves, thereby reinforcing the cascade activation between caspase-3/GSDME-dependent pyroptosis and cGAS-STING signaling pathway. This lysosomal disruption-nanobomb represents a new strategy for advancing GBM immunotherapy.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"5 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146122","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 : 2026-02-10DOI: 10.1016/j.jconrel.2026.114714
Jinfan Yang, Jiachen Wang, Ning Shang, Ji Xu, Chunju Lou, Xin Zhou, Miyao Sun, Xiaoyu Guang, Sitong Zhao, Yang Zhang, Siyuan Wang, Jiayu Xie, Fang Chen, Baishun Liu, Chuhan Qiang, Wenxi Lei, Wentao Su, Mingzhen Zhang, Wenyi Zhang, Zhihong Sun, Hao Wu, Mingqian Tan, Xiaobin Ma
Probiotics alleviate symptoms of inflammatory bowel disease (IBD), metabolic disorders, and cardiovascular disorders by modulating the gut microbiota. However, oral probiotics face significant survival challenges due to the protective environment of the gastrointestinal tract. Inspired by the strong reparative properties and adhesive features of slug mucus, we developed a biomimetic universal single-cell coated probiotics system (AC-EcN), and the single-cell coating provides strong adhesion, durability, and self-healing after shear stress, with a double-layer network structure. Consequently, it provides prolonged protection (over 96 h) against gastrointestinal barriers, significantly enhancing probiotic proliferation in the intestines and achieving sustained cumulative effects with multiple oral administrations. Additionally, AC-EcN can selectively aggregate in response to inflammation, thereby amplifying the therapeutic benefits of probiotics. This process modulates intestinal inflammation, rapidly restores intestinal barrier function, and alters intestinal microbial community structure. Fundamentally reestablishing a healthy colonic state and reversing IBD. This probiotic single-cell coating strategy, which improves probiotic colonization efficiency, significantly enhances the treatment of IBD as a universal approach to potentiate orally administered probiotics.
{"title":"Slug-mucus-inspired single-cell coating enhances the treatment of inflammatory bowel disease by improving probiotic colonization efficiency","authors":"Jinfan Yang, Jiachen Wang, Ning Shang, Ji Xu, Chunju Lou, Xin Zhou, Miyao Sun, Xiaoyu Guang, Sitong Zhao, Yang Zhang, Siyuan Wang, Jiayu Xie, Fang Chen, Baishun Liu, Chuhan Qiang, Wenxi Lei, Wentao Su, Mingzhen Zhang, Wenyi Zhang, Zhihong Sun, Hao Wu, Mingqian Tan, Xiaobin Ma","doi":"10.1016/j.jconrel.2026.114714","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114714","url":null,"abstract":"Probiotics alleviate symptoms of inflammatory bowel disease (IBD), metabolic disorders, and cardiovascular disorders by modulating the gut microbiota. However, oral probiotics face significant survival challenges due to the protective environment of the gastrointestinal tract. Inspired by the strong reparative properties and adhesive features of slug mucus, we developed a biomimetic universal single-cell coated probiotics system (AC-EcN), and the single-cell coating provides strong adhesion, durability, and self-healing after shear stress, with a double-layer network structure. Consequently, it provides prolonged protection (over 96 h) against gastrointestinal barriers, significantly enhancing probiotic proliferation in the intestines and achieving sustained cumulative effects with multiple oral administrations. Additionally, AC-EcN can selectively aggregate in response to inflammation, thereby amplifying the therapeutic benefits of probiotics. This process modulates intestinal inflammation, rapidly restores intestinal barrier function, and alters intestinal microbial community structure. Fundamentally reestablishing a healthy colonic state and reversing IBD. This probiotic single-cell coating strategy, which improves probiotic colonization efficiency, significantly enhances the treatment of IBD as a universal approach to potentiate orally administered probiotics.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"247 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146640","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 : 2026-02-09DOI: 10.1016/j.jconrel.2026.114711
Amin Ariaee, Karim Noueihad, Alex Hunter, Anthony Wignall, Hannah R. Wardill, Maya Davies, Clive A. Prestidge, Paul Joyce
Semaglutide (SEM) is a glucagon-like peptide-1 (GLP-1) receptor agonist formulated for oral delivery with the absorption enhancer salcaprozate sodium (SNAC). Although oral SEM achieves 0.4–1% bioavailability through gastric epithelial uptake, gastrointestinal (GI) adverse events remain a major cause of therapy discontinuation. This study examined the effects of SEM (0.74 mg/kg/day), SNAC (22 mg/kg/day), and combined SEM–SNAC (1:33 w/w) treatments on microbiota and metabolic function, in healthy Sprague Dawley rats over 21 days. Whilst microbial α-diversity remained stable, SNAC significantly altered β-diversity (PERMANOVA, p < 0.05) and depleted primary fermenters in Muribaculaceae (−62%) and Bacteroidaceae (−77%) compared to the control group. These compositional changes correlated with reduced predicted saccharolytic enzyme abundance and fecal butyrate concentrations (−77% SNAC, −75% SEM–SNAC). Plasma cytokine analysis showed elevated tumor necrosis factor-α (TNF-α, 70%) and suppressed brain-derived neurotrophic factor (BDNF, 85%), consistent with changes in circulating inflammatory and neurotrophic markers from SNAC monotherapy. SNAC-treated animals also exhibited increased liver weight and reduced caecum mass, occurring alongside microbiota compositional changes and altered fermentation-associated markers. Spearman correlations linked Muribaculaceae and Bacteroidaceae loss with decreased saccharolytic enzyme abundance, lower SCFA levels, and increased TNF-α. While these findings are associative and require mechanistic validation, they indicate that chronic SNAC exposure is linked to concurrent microbial, metabolic, and inflammatory marker changes in healthy rats, highlighting the potential need for alternative, microbiota-safe strategies for oral peptide delivery.
{"title":"Gut microbiota perturbation and systemic inflammation are associated with salcaprozate sodium (SNAC)-enabled oral semaglutide delivery","authors":"Amin Ariaee, Karim Noueihad, Alex Hunter, Anthony Wignall, Hannah R. Wardill, Maya Davies, Clive A. Prestidge, Paul Joyce","doi":"10.1016/j.jconrel.2026.114711","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114711","url":null,"abstract":"Semaglutide (SEM) is a glucagon-like peptide-1 (GLP-1) receptor agonist formulated for oral delivery with the absorption enhancer salcaprozate sodium (SNAC). Although oral SEM achieves 0.4–1% bioavailability through gastric epithelial uptake, gastrointestinal (GI) adverse events remain a major cause of therapy discontinuation. This study examined the effects of SEM (0.74 mg/kg/day), SNAC (22 mg/kg/day), and combined SEM–SNAC (1:33 <ce:italic>w</ce:italic>/w) treatments on microbiota and metabolic function, in healthy Sprague Dawley rats over 21 days. Whilst microbial α-diversity remained stable, SNAC significantly altered β-diversity (PERMANOVA, <ce:italic>p</ce:italic> < 0.05) and depleted primary fermenters in <ce:italic>Muribaculaceae</ce:italic> (−62%) and <ce:italic>Bacteroidaceae</ce:italic> (−77%) compared to the control group. These compositional changes correlated with reduced predicted saccharolytic enzyme abundance and fecal butyrate concentrations (−77% SNAC, −75% SEM–SNAC). Plasma cytokine analysis showed elevated tumor necrosis factor-α (TNF-α, 70%) and suppressed brain-derived neurotrophic factor (BDNF, 85%), consistent with changes in circulating inflammatory and neurotrophic markers from SNAC monotherapy. SNAC-treated animals also exhibited increased liver weight and reduced caecum mass, occurring alongside microbiota compositional changes and altered fermentation-associated markers. Spearman correlations linked <ce:italic>Muribaculaceae</ce:italic> and <ce:italic>Bacteroidaceae</ce:italic> loss with decreased saccharolytic enzyme abundance, lower SCFA levels, and increased TNF-α. While these findings are associative and require mechanistic validation, they indicate that chronic SNAC exposure is linked to concurrent microbial, metabolic, and inflammatory marker changes in healthy rats, highlighting the potential need for alternative, microbiota-safe strategies for oral peptide delivery.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"160 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146641","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 : 2026-02-09DOI: 10.1016/j.jconrel.2026.114699
Peyton M. Panovich, Aditi Ganesan, Arianna I. Markey, Miriam E. Stevens, Owen M. Kelly, Alexandra S. Piotrowski-Daspit
Polymeric nanoparticles (NPs) are a versatile delivery platform for non-viral genetic therapies. However, a key shortcoming of polymeric NPs (and other non-viral delivery vehicles) is the often-high accumulation of NPs within the liver and the spleen after systemic intravenous (IV) administration in vivo. This phenomenon is largely the result of the mononuclear phagocytic system (MPS), a class of phagocytic cells responsible for native immune response and toxin clearance within the body. One strategy to overcome NP clearance by the MPS is the use of phagocytic modulating pre-treatments to intentionally and temporarily alter the phagocytic behavior of macrophages such that sequentially administered therapeutic NPs can be delivered to extrahepatic and extrasplenic tissues. Here, we explore the use cargo-free poly(lactic-co-glycolic acid) (PLGA) “decoy” NPs as pre-treatments for phagocytic evasion of sequentially administered therapeutic NPs. Analysis via flow cytometry and fluorescence microscopy reveal that cargo-free PLGA NPs significantly decrease uptake of subsequently administered therapeutic NPs by macrophages. Specifically, we conclude that variables such as size, surfactant composition, and timing of pre-treatment influence the behavior of cargo-free PLGA decoy NPs in modulating phagocytic activity of macrophages. In in vivo studies, we report decreased accumulation in the liver and increased deposition of therapeutic NPs in the lung with pre-administration of cargo-free decoy PLGA NPs. Together, these studies suggest pre-treatment with decoy NPs can reduce therapeutic NP clearance, with the potential to improve nanomedicine delivery capabilities for a wide range of therapeutics and disease targets.
{"title":"Engineered cargo-free nanoparticle decoys for phagocytic modulation of macrophages","authors":"Peyton M. Panovich, Aditi Ganesan, Arianna I. Markey, Miriam E. Stevens, Owen M. Kelly, Alexandra S. Piotrowski-Daspit","doi":"10.1016/j.jconrel.2026.114699","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114699","url":null,"abstract":"Polymeric nanoparticles (NPs) are a versatile delivery platform for non-viral genetic therapies. However, a key shortcoming of polymeric NPs (and other non-viral delivery vehicles) is the often-high accumulation of NPs within the liver and the spleen after systemic intravenous (IV) administration in vivo. This phenomenon is largely the result of the mononuclear phagocytic system (MPS), a class of phagocytic cells responsible for native immune response and toxin clearance within the body. One strategy to overcome NP clearance by the MPS is the use of phagocytic modulating pre-treatments to intentionally and temporarily alter the phagocytic behavior of macrophages such that sequentially administered therapeutic NPs can be delivered to extrahepatic and extrasplenic tissues. Here, we explore the use cargo-free poly(lactic-<ce:italic>co</ce:italic>-glycolic acid) (PLGA) “decoy” NPs as pre-treatments for phagocytic evasion of sequentially administered therapeutic NPs. Analysis via flow cytometry and fluorescence microscopy reveal that cargo-free PLGA NPs significantly decrease uptake of subsequently administered therapeutic NPs by macrophages. Specifically, we conclude that variables such as size, surfactant composition, and timing of pre-treatment influence the behavior of cargo-free PLGA decoy NPs in modulating phagocytic activity of macrophages. In in vivo studies, we report decreased accumulation in the liver and increased deposition of therapeutic NPs in the lung with pre-administration of cargo-free decoy PLGA NPs. Together, these studies suggest pre-treatment with decoy NPs can reduce therapeutic NP clearance, with the potential to improve nanomedicine delivery capabilities for a wide range of therapeutics and disease targets.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"46 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146642","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 : 2026-02-09DOI: 10.1016/j.jconrel.2026.114675
Joanna Kopecka, Ivana Campia, Paolo Olivero, Gianpiero Pescarmona, Dario Ghigo, Amalia Bosia, Chiara Riganti
{"title":"Corrigendum to ‘A LDL-masked liposomal-doxorubicin reverses drug resistance in human cancer cells’ [Journal of Controlled Release 149(2) (2011) 196–205]","authors":"Joanna Kopecka, Ivana Campia, Paolo Olivero, Gianpiero Pescarmona, Dario Ghigo, Amalia Bosia, Chiara Riganti","doi":"10.1016/j.jconrel.2026.114675","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114675","url":null,"abstract":"","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"59 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146643","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 : 2026-02-09DOI: 10.1016/j.jconrel.2026.114685
Huai Yang, Jing-Long Hu, Yunjun Xu, Tian-Ci Sun, Xu Yan, Haojie Lu, Dongquan Liu, Baoqiang Cao, Yang Lu, Tao He
Percutaneous locoregional drug injection based on hydrogel therapy under image guidance is performed to limit the progression of hepatocellular carcinoma (HCC) and extend the waiting time for liver transplantation patients. However, achieving uniform distribution and sustained retention of drugs within the tumor bed remains a critical bottleneck urgently requiring breakthroughs in the current field of oncology. Here, an acid-labile thermosensitive hydrogel (denoted as NCD) with efficient magnetothermal functionality was developed by incorporating iron oxide nanoparticles (CION) and DOX into the ortho-ester-functionalized thermosensitive polymer matrix (poly(N-isopropylacrylamide270)-ortho ester-poly(ethylene glycol)). Engineered for multimodal therapy, the NCD hydrogel utilized an acid-cleavable backbone to achieve sustained DOX release (77.4 ± 2.1% at pH 6.5, 72 h), markedly exceeding the control release of 26.8 ± 2.7% and yielding uniform tumor drug distribution. Its thermosensitive PNIPAM matrix (LCST ≈ 32 °C) enabled injectable sol-gel transition at body temperature, allowing easy administration (maximum injection pressure: merely 6.0 ± 0.3 N) and forming a depot for prolonged drug retention. Combined with CION-enhanced magnetothermal therapy, ultrasound-guided NCD delivery suppressed orthotopic liver tumor growth, positioning it as a promising bridging strategy to transplantation.
{"title":"Injectable acid-labile thermosensitive magnetic hydrogel with responsive drug release for bridging liver transplantation in hepatocellular carcinoma","authors":"Huai Yang, Jing-Long Hu, Yunjun Xu, Tian-Ci Sun, Xu Yan, Haojie Lu, Dongquan Liu, Baoqiang Cao, Yang Lu, Tao He","doi":"10.1016/j.jconrel.2026.114685","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114685","url":null,"abstract":"Percutaneous locoregional drug injection based on hydrogel therapy under image guidance is performed to limit the progression of hepatocellular carcinoma (HCC) and extend the waiting time for liver transplantation patients. However, achieving uniform distribution and sustained retention of drugs within the tumor bed remains a critical bottleneck urgently requiring breakthroughs in the current field of oncology. Here, an acid-labile thermosensitive hydrogel (denoted as NCD) with efficient magnetothermal functionality was developed by incorporating iron oxide nanoparticles (CION) and DOX into the ortho-ester-functionalized thermosensitive polymer matrix (poly(<ce:italic>N</ce:italic>-isopropylacrylamide<ce:inf loc=\"post\">270</ce:inf>)-ortho ester-poly(ethylene glycol)). Engineered for multimodal therapy, the NCD hydrogel utilized an acid-cleavable backbone to achieve sustained DOX release (77.4 ± 2.1% at pH 6.5, 72 h), markedly exceeding the control release of 26.8 ± 2.7% and yielding uniform tumor drug distribution. Its thermosensitive PNIPAM matrix (LCST ≈ 32 °C) enabled injectable sol-gel transition at body temperature, allowing easy administration (maximum injection pressure: merely 6.0 ± 0.3 N) and forming a depot for prolonged drug retention. Combined with CION-enhanced magnetothermal therapy, ultrasound-guided NCD delivery suppressed orthotopic liver tumor growth, positioning it as a promising bridging strategy to transplantation.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"89 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146631","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}
Age-related nicotinamide adenine dinucleotide (NAD+) deficiency is implicated in numerous pathologies, including dry age-related macular degeneration (AMD). Current NAD+-boosting strategies, reliant on precursors like nicotinamide mononucleotide (NMN), necessitate repeated dosing and offer transient effects, limiting therapeutic utility. Here, we address this critical limitation by developing a single-dose therapy using circular mRNA (circ-mRNA) to deliver functional nicotinamide phosphoribosyl transferase (NAMPT), the essential rate-limiting enzyme in NAD+ salvage. Engineered via permuted intron-exon (PIE) splicing, our circNAMPT exploits the exceptional stability and persistent translation capacity inherent to circular RNA scaffolds. Encapsulation in β-sitosterol-optimized lipid nanoparticles (LNPs) ensures robust intracellular delivery. In vitro, circNAMPT-LNP drives sustained NAMPT expression and prolonged NAD+ elevation, circumventing precursor limitations. In a stringent sodium iodate-induced dry AMD model, a single intravitreal circNAMPT-LNP injection matched the neuroprotective efficacy of 14 consecutive daily intraperitoneal NMN doses confirmed by histological integrity and functional preservation. This work establishes engineered circ-mRNAs as a transformative platform for durable, single-dose therapeutic protein delivery, demonstrates potential as a disease-modifying therapy for dry AMD. Its applicability extends broadly to systemic disorders driven by NAD+ deficiency in aging.
{"title":"Single intravitreal injection of lipid nanoparticles delivering circular mRNA of nicotinamide phosphoribosyltransferase protects against dry AMD","authors":"Hui-Lin Li, Yu Xu, Jian-Shan Mo, Xin-Yuan Zhao, Cai-Ling Zhong, Zi-Wen Jia, Xiao-Long Wang, Ben-Chi Zhao, Yan-Ming Chen, Ke-Wei Zheng, Xiao-Lei Zhang, Qiao-Ping Wang","doi":"10.1016/j.jconrel.2026.114691","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114691","url":null,"abstract":"Age-related nicotinamide adenine dinucleotide (NAD<sup>+</sup>) deficiency is implicated in numerous pathologies, including dry age-related macular degeneration (AMD). Current NAD<sup>+</sup>-boosting strategies, reliant on precursors like nicotinamide mononucleotide (NMN), necessitate repeated dosing and offer transient effects, limiting therapeutic utility. Here, we address this critical limitation by developing a single-dose therapy using circular mRNA (circ-mRNA) to deliver functional nicotinamide phosphoribosyl transferase (NAMPT), the essential rate-limiting enzyme in NAD<sup>+</sup> salvage. Engineered via permuted intron-exon (PIE) splicing, our circNAMPT exploits the exceptional stability and persistent translation capacity inherent to circular RNA scaffolds. Encapsulation in β-sitosterol-optimized lipid nanoparticles (LNPs) ensures robust intracellular delivery. In vitro, circNAMPT-LNP drives sustained NAMPT expression and prolonged NAD<sup>+</sup> elevation, circumventing precursor limitations. In a stringent sodium iodate-induced dry AMD model, a single intravitreal circNAMPT-LNP injection matched the neuroprotective efficacy of 14 consecutive daily intraperitoneal NMN doses confirmed by histological integrity and functional preservation. This work establishes engineered circ-mRNAs as a transformative platform for durable, single-dose therapeutic protein delivery, demonstrates potential as a disease-modifying therapy for dry AMD. Its applicability extends broadly to systemic disorders driven by NAD<sup>+</sup> deficiency in aging.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"568 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138283","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 : 2026-02-08DOI: 10.1016/j.jconrel.2026.114709
Yuichi Suzuki, Yuma Yamada, Hideyoshi Harashima, Yusuke Sato
Ionizable lipids enable lipid nanoparticles (LNPs) to deliver nucleic acids, including mRNA, to target cells. However, the efficiency of the endosomal escape of conventional LNPs remains limited to a small percentage. Lipid components that actively interact with net-neutral phospholipids in endosomal membranes and promote membrane fusion potentially enhance the efficiency of endosomal escape and further improve functional mRNA delivery. In this study, we developed a zwitterionic tri-oleoyl-Tris (zTOT) library and used it to enhance mRNA delivery by replacing the widely used helper lipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) in LNPs with zTOT. LNPs containing TOT-15, an example of zTOT, demonstrated a 5-fold higher gene expression compared with that of DSPC-LNPs. TOT-15-LNPs composed of commercially available ionizable lipids showed enhanced gene expression compared with that of DSPC-LNPs. The TOT-15-LNPs also showed almost 100% gene knockout efficiency with no toxicity. The TOT-15 system interacts with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and induces a non-lamellar structure. Pharmacokinetic calculation revealed that endosomal escape efficiency of the TOT-15-LNPs was more than 9.6%. In summary, the results of this study demonstrate that the zTOT system enhances the efficiency of both endosomal escape and functional mRNA delivery.
可电离脂质使脂质纳米颗粒（LNPs）能够将核酸（包括mRNA）递送到靶细胞。然而，传统LNPs的内体逃逸效率仍然局限于很小的百分比。与内体膜中净中性磷脂积极相互作用并促进膜融合的脂质成分可能提高内体逃逸效率并进一步改善mRNA的功能性传递。在这项研究中，我们建立了一个两性离子三油酰三（zTOT）文库，并用zTOT取代LNPs中广泛使用的辅助脂质1,2-二硬脂酰- san -甘油-3-磷酸胆碱（dsc）来增强mRNA的传递。以zTOT为例，含有TOT-15的LNPs的基因表达量比含有DSPC-LNPs的LNPs高5倍。由市售可电离脂质组成的TOT-15-LNPs与DSPC-LNPs相比，基因表达增强。TOT-15-LNPs也显示出几乎100%的基因敲除效率，而且没有毒性。TOT-15体系与1-棕榈酰-2-油基- cn -甘油-3-磷酸胆碱（POPC）相互作用，诱导出非层状结构。药代动力学计算表明，TOT-15-LNPs的内体逃逸效率大于9.6%。总之，本研究的结果表明，zTOT系统提高了内体逃逸和功能性mRNA传递的效率。
{"title":"Lipid nanoparticles containing zwitterionic lipids versatilely enhance the efficiency of mRNA delivery","authors":"Yuichi Suzuki, Yuma Yamada, Hideyoshi Harashima, Yusuke Sato","doi":"10.1016/j.jconrel.2026.114709","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114709","url":null,"abstract":"Ionizable lipids enable lipid nanoparticles (LNPs) to deliver nucleic acids, including mRNA, to target cells. However, the efficiency of the endosomal escape of conventional LNPs remains limited to a small percentage. Lipid components that actively interact with net-neutral phospholipids in endosomal membranes and promote membrane fusion potentially enhance the efficiency of endosomal escape and further improve functional mRNA delivery. In this study, we developed a zwitterionic tri-oleoyl-Tris (zTOT) library and used it to enhance mRNA delivery by replacing the widely used helper lipid 1,2-distearoyl-<ce:italic>sn</ce:italic>-glycero-3-phosphocholine (DSPC) in LNPs with zTOT. LNPs containing TOT-15, an example of zTOT, demonstrated a 5-fold higher gene expression compared with that of DSPC-LNPs. TOT-15-LNPs composed of commercially available ionizable lipids showed enhanced gene expression compared with that of DSPC-LNPs. The TOT-15-LNPs also showed almost 100% gene knockout efficiency with no toxicity. The TOT-15 system interacts with 1-palmitoyl-2-oleoyl-<ce:italic>sn</ce:italic>-glycero-3-phosphocholine (POPC) and induces a non-lamellar structure. Pharmacokinetic calculation revealed that endosomal escape efficiency of the TOT-15-LNPs was more than 9.6%. In summary, the results of this study demonstrate that the zTOT system enhances the efficiency of both endosomal escape and functional mRNA delivery.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"51 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146644","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}
Extracellular vesicles (EVs) are now seen as powerful tools for next-generation diagnostics, targeted drug delivery, and cell-free therapies. Their clinical application, however, is constrained by storage challenges—the preservation process compromises their structure and activity. This review summarizes current methods for preserving EVs, including cryopreservation, spray-drying, and freeze-drying. It also discusses how suboptimal storage conditions affect the critical quality attributes (CQAs) of EVs, including membrane integrity, cargo stability, biological activity, immunogenicity, and recovery efficiency. This review adopts an application-oriented approach, highlighting the distinct stability requirements for EVs serving as diagnostic markers, delivery vehicles, or therapeutic agents. Furthermore, it also evaluated new optimization strategies, such as a reasonable cryopreservation protective agent formulation, an improved buffer solution formulation, reduced adsorption storage materials, and advanced material-based stable technologies. Finally, this review outlines the future directions, emphasizing the need to adopt standardized and scalable preservation methods that are oriented towards EV clinical applications, to accelerate the transition of EV-based technologies from the laboratory to clinical practice.
{"title":"A comprehensive review on the storage stability of extracellular vesicles for clinical translation: Current status, challenges, and prospects","authors":"Hai Huang, Wenjie Xu, Xinyan Hao, Pengcheng Sun, Mengen Guo, Muyan Li, Xinying Liu, Yanjin Peng, Ruyue Han, Tiantian Tang, Yucheng Tang, Daxiong Xiang, Ming Wang, Junyong Wu","doi":"10.1016/j.jconrel.2026.114706","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114706","url":null,"abstract":"Extracellular vesicles (EVs) are now seen as powerful tools for next-generation diagnostics, targeted drug delivery, and cell-free therapies. Their clinical application, however, is constrained by storage challenges—the preservation process compromises their structure and activity. This review summarizes current methods for preserving EVs, including cryopreservation, spray-drying, and freeze-drying. It also discusses how suboptimal storage conditions affect the critical quality attributes (CQAs) of EVs, including membrane integrity, cargo stability, biological activity, immunogenicity, and recovery efficiency. This review adopts an application-oriented approach, highlighting the distinct stability requirements for EVs serving as diagnostic markers, delivery vehicles, or therapeutic agents. Furthermore, it also evaluated new optimization strategies, such as a reasonable cryopreservation protective agent formulation, an improved buffer solution formulation, reduced adsorption storage materials, and advanced material-based stable technologies. Finally, this review outlines the future directions, emphasizing the need to adopt standardized and scalable preservation methods that are oriented towards EV clinical applications, to accelerate the transition of EV-based technologies from the laboratory to clinical practice.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"91 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134050","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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