Drug Delivery最新文献

{"title":"A systematic review of liposomal nanofibrous scaffolds as a drug delivery system: a decade of progress in controlled release and therapeutic efficacy.","authors":"Houssam Aaref Abboud, Romána Zelkó, Adrienn Kazsoki","doi":"10.1080/10717544.2024.2445259","DOIUrl":"https://doi.org/10.1080/10717544.2024.2445259","url":null,"abstract":"<p><p>Drug-loaded liposomes incorporated in nanofibrous scaffolds is a promising approach as a multi-unit nanoscale system, which combines the merits of both liposomes and nanofibers (NFs), eliminating the drawback of liposomes' poor stability on the one hand and offering a higher potential of controlled drug release and enhanced therapeutic efficacy on the other hand. The current systematic review, which underwent a rigorous search process in PubMed, Web of Science, Scopus, Embase, and Central (Cochrane) employing (Liposome AND nanofib* AND electrosp*) as search keywords, aims to present the recent studies on using this synergic system for different therapeutic applications. The search was restricted to original, peer-reviewed studies published in English between 2014 and 2024. Of the 309 identified records, only 29 studies met the inclusion criteria. According to the literature, three different methods were identified to fabricate those nanofibrous liposomal scaffolds. The results consistently demonstrated the superiority of this dual system for numerous therapeutic applications in improving the therapy efficacy, enhancing both liposomes and drug stability, and releasing the encapsulated drug in a proper sustained release without significant initial burst release. Merging drug-loaded liposomes with NFs as liposomal nanofibrous scaffolds are a safe and efficient approach to deliver drug molecules and other substances for various pharmaceutical applications, particularly for wound dressing, tissue engineering, cancer therapy, and drug administration <i>via</i> the buccal and sublingual routes. However, further research is warranted to explore the potential of this system in other therapeutic applications.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2445259"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADAMTS5-specific gapmer release from an albumin biomolecular assembly and cartilage internalization triggered by ultrasound.","authors":"Marwa Elkhashab, Goncalo Barreto, Maxime Fauconnier, Yohann Le Bourlout, Laura B Creemers, Heikki J Nieminen, Kenneth A Howard","doi":"10.1080/10717544.2025.2464921","DOIUrl":"10.1080/10717544.2025.2464921","url":null,"abstract":"<p><strong>Objective: </strong>Antisense oligonucleotides (ASOs) have reached the clinic; however, they lack tissue specificity. Albumin is a plasma-abundant macromolecule that has been shown to accumulate in inflamed tissues. In this work, we have designed a recombinant human albumin (rHA)-based biomolecular assembly incorporating a DNase-resistant phosphorothioate-based complementary oligonucleotide (cODN) and an anti-ADAMTS5 ASO for potential delivery to inflamed sites. Ultrasound (US) was used to trigger ASO release from the assembly and enhance internalization into articular cartilage.</p><p><strong>Methods: </strong>A phosphorothioate cODN was conjugated to rHA through a maleimide cross-linker after which, a therapeutic ADAMTS5-specific gapmer ASO was annealed to the cODN. ASO release was assessed after exposing the biomolecular assembly to different US conditions using an US-actuated medical needle operating at 32.2 kHz. Gene silencing efficiency of US-treated anti-ADAMTS5 ASO was assessed in human primary chondrocytes isolated from osteoarthritic patients. US-mediated ASO penetration into articular cartilage was assessed on <i>ex vivo</i> bovine articular cartilage.</p><p><strong>Results: </strong>ASO release was observed after exposure to US waves in continuous mode conditions that did not compromise ASO gene silencing efficiency in human chondrocytes. Furthermore, US increased ASO internalization into bovine articular cartilage after 30 min of application without detrimental effects on chondrocyte viability.</p><p><strong>Conclusion: </strong>A medical needle driven by continuous US waves at 32.2 kHz has the capability of disassembling a duplex oligonucleotide and enhancing released ASOs internalization into articular cartilage. This work offers the potential delivery and the local triggered release of ASOs at the surface of articular cartilage providing potential benefits for the treatment of diverse cartilage pathologies.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2464921"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploiting the potential of <i>in situ</i> forming liquid crystals: development and <i>in vitro</i> performance of long-acting depots for peptide drug thymosin alpha 1 subcutaneous administration.","authors":"Mercedes Vitek, Alenka Zvonar Pobirk, Robert Roškar, Mirjam Gosenca Matjaž","doi":"10.1080/10717544.2025.2460708","DOIUrl":"10.1080/10717544.2025.2460708","url":null,"abstract":"<p><p>The fast-growing filed of long-acting depots for subcutaneous (SC) administration holds significant potential to enhance patient adherence to treatment regimens, particularly in the context of chronic diseases. Among them, injectable <i>in situ</i> forming lyotropic liquid crystals (LCCs) consisting of hexagonal mesophases represent an attractive platform due to their remarkable highly ordered microstructure enabling the sustained drug release. These systems are especially relevant for peptide drugs, as their use is limited by their short plasma half-life and inherent poor stability. In this study, we thus aimed to exploit the potential of a liquid crystalline platform for the sustained release of peptide drug thymosin alpha 1 (Tα1), characterized by a short plasma half-life and with that associated twice-weekly SC administration regimen. We initially selected specified ingredients, with ethanol serving to reduce viscosity and stabilize the peptide drug Tα1, lecithin contributing to LCCs formation and stabilization, and glycerol monooleate or glycerol monolinoleate representing the hexagonal LCCs forming matrix material. The selected studied nonaqueous precursor formulations were characterized by suitable rheological properties for SC injection. A convenient and rapid <i>in situ</i> phase transition of precursor formulations to hexagonal LCCs, triggered by water absorption, was successfully accomplished <i>in vitro.</i> Notably, <i>in situ</i> formed LCCs demonstrated sustained release kinetics of the peptide drug Tα1 for up to 2 weeks of <i>in vitro</i> release testing, offering minimized dosing frequency and thus promoting patient adherence. In summary, the newly developed <i>in situ</i> forming liquid crystalline systems represent prospective injectable long-acting depots for SC administration of the peptide drug Tα1.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2460708"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating nurse preferences for a novel on-body delivery system vs. manual syringes for large-volume subcutaneous drug administration: a survey study.","authors":"Mehul Desai, Beth Faiman, Lisa A Gorski, Ashley Miles, Valentina Sterlin, Nicole Curry","doi":"10.1080/10717544.2025.2484278","DOIUrl":"10.1080/10717544.2025.2484278","url":null,"abstract":"<p><p>While nurses report challenges with the manual administration of large-volume subcutaneous drugs, these challenges and potential solutions are not captured in the literature. In this cross-sectional study, 45 nurses with experience administering large-volume subcutaneous biologics completed an 18-item survey about preferences for syringes vs. on-body delivery systems. 100% responded that an on-body delivery system seemed easy to learn and use and preferable to syringes. In a drug delivery scenario including comprehensive administration details and assuming equivalent safety and efficacy, 97.78% preferred the on-body delivery system to a daratumumab/hyaluronidase syringe. In the total sample, this preference was primarily attributed to (1) reduced nurse effort due to hands-free delivery, (2) decreased patient pain due to a thinner needle, (3) elimination of needlestick injuries due to a hidden needle, and (4) increased clinic efficiency due to hands-free delivery. 95.56% felt that the on-body delivery system would improve clinic throughput better than syringes. Nurses reported that an on-body delivery system would be easy to learn and use and would improve clinic efficiency and safety. They underscored the importance of decreasing nurse physical burden, needlestick injuries, and patient needle phobia. Contrary to the assumption that speed is paramount, nurses prioritized reducing effort, enhancing administration safety, and improving patient comfort over injection speed.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2484278"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptides rapidly transport antibiotic across the intact tympanic membrane to treat a middle ear infection.","authors":"Arwa Kurabi, Emily Sereno, Allen F Ryan","doi":"10.1080/10717544.2025.2463427","DOIUrl":"10.1080/10717544.2025.2463427","url":null,"abstract":"<p><p>The tympanic membrane (TM) forms an impenetrable barrier to medical therapies for middle ear (ME) diseases like otitis media. By screening a phage-displayed peptide library, we have previously discovered rare peptides that mediate the active transport of cargo across the intact membrane of animals and humans. Since the M13 filamentous bacteriophage on which the peptides are expressed are large (nearly 1 µm in length), this offers the possibility of noninvasively delivering drugs, large drug packages, or gene therapy to the ME. To evaluate this possibility, EDC chemistry was employed to covalently attach amoxicillin, or neomycin molecules to phage bearing a trans-TM peptide, as a model for large drug packages. Eight hours after application of antibiotic-phage to the TM of infected rats, ME bacterial titers were substantially reduced compared to untreated animals. As a control, antibiotic was linked to wild-type phage, not bearing any peptide, and application to the TM did not affect ME bacteria. The results support the ability of rare peptides to actively deliver pharmacologically relevant amounts of drugs through the intact TM and into the ME. Moreover, since bacteriophage engineered to express peptides are viral vectors, the trans-TM peptides could also transport other viral vectors into the ME.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2463427"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of nebulizers on nanoparticles-based gene delivery efficiency: <i>in vitro</i> and <i>in vivo</i> comparison of jet and mesh nebulizers using branched-polyethyleneimine.","authors":"Rosy Ghanem, Xavier Buin, Tanguy Haute, Justine Philippe, Ghalia Kaouane, Lara Leclerc, Maël Guivarch, Tony Le Gall, Jérémie Pourchez, Tristan Montier","doi":"10.1080/10717544.2025.2463428","DOIUrl":"10.1080/10717544.2025.2463428","url":null,"abstract":"<p><p>Nanoparticles-based gene delivery has emerged as a promising approach for the treatment of genetic diseases based on efficient delivery systems for therapeutic nucleic acids (NAs) into the target cells. For pulmonary diseases such as cystic fibrosis (CF), chronic obstructive pulmonary diseases (COPD), infectious disease or lung cancer, aerosol delivery is the best choice to locally deliver NAs into the lungs. It is, therefore, important to investigate the effects of nebulization conditions on the efficiency of delivery. To this purpose, the non-viral vector branched polyethyleneimine (b-PEI, 25 kDa) was investigated for plasmid delivery by aerosol. Two types of nebulizers, jet nebulizer and mesh nebulizer, were compared regarding the properties of the nanoparticles (NPs) formed, the efficiency of NAs delivery <i>in vitro</i> and <i>in vivo</i> models and the pulmonary deposition. The results indicate that the mesh nebulizer has a better gene delivery performance than the jet nebulizer in this application. This superiority was demonstrated in terms of size, concentration, distribution of NPs and efficiency of NAs delivery. However, pulmonary deposition appears to be similar regardless of the nebulizer used, and the difference between the two systems lies in the inhalable dose. These results underline the crucial role of nebulization techniques in optimizing aerosol-mediated gene delivery by b-PEI and highlight the potential of mesh nebulizers as promising tools to improved gene therapy. Therefore, the comparison must be performed for each gene therapy formulation to determine the most suitable nebulizer.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2463428"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11816613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and biocompatibility of a novel biodegradable aflibercept-drug delivery system in rhesus macaques.","authors":"Brett D Story, Sangwan Park, Karolina Roszak, Jaeho Shim, Monica Motta, Michelle Ferneding, Kayla M Rudeen, Andrew Blandino, Monica Ardon, Sophie Le, Leandro B C Teixeira, Glenn Yiu, William F Mieler, Sara M Thomasy, Jennifer J Kang-Mieler","doi":"10.1080/10717544.2025.2460671","DOIUrl":"10.1080/10717544.2025.2460671","url":null,"abstract":"<p><p>A clinical need exists for more effective intravitreal (IVT) drug delivery systems (DDS). This study tested the hypothesis that a novel biodegradable, injectable microsphere-hydrogel drug delivery system loaded with aflibercept (aflibercept-DDS) would exhibit long-term safety and biocompatibility in a non-human primate (NHP) model. We generated aflibercept-loaded poly (lactic-co-glycolic acid) microparticles with a modified double emulsion technique then embedded them into a biodegradable, thermo-responsive poly (ethylene glycol)-co-(L-lactic-acid) diacrylate/N-isopropylacrylamide hydrogel. Aflibercept-DDS (50 µL, 15 µg) was injected into the right eye of 23 healthy rhesus macaques. A complete ophthalmic examination, intraocular pressure (IOP), corneal pachymetry, specular microscopy, A-scan biometry, streak retinoscopy, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and electroretinography (ERG) were performed monthly. Globes from 7 NHPs were histologically examined. Aflibercept-DDS was visualized in the vitreous up to 9 months post-IVT injection, slightly impeding fundoscopy in 4 of 23 eyes; no other consistent abnormalities were appreciated during ophthalmic examination. The IOP and total retinal thickness remained normal in all animals over all timepoints. Central corneal thickness, endothelial cell density, axial globe length, and refractive error did not significantly differ from baseline. Scotopic mixed rod-cone implicit times and amplitudes along with photopic cone response implicit times and amplitudes did not significantly differ from control values. No retinal or choroidal vascular abnormalities were detected with FA and normal retinal architecture was preserved using SD-OCT. Intravitreal injection of a biodegradable aflibercept-DDS was safe and well tolerated in NHPs up to 24 months.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2460671"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orchestrating T and NK cells for tumor immunotherapy via NKG2A-targeted delivery of a de novo designed IL-2Rβγ agonist.","authors":"Jie Chen, Enhui Ren, Ze Tao, Hongyu Lu, Yunchuan Huang, Jing Li, Yuzhe Chen, Zhuo Chen, Tianshan She, Hao Yang, Hong Zhu, Xiaofeng Lu","doi":"10.1080/10717544.2025.2482195","DOIUrl":"10.1080/10717544.2025.2482195","url":null,"abstract":"<p><p>As T and NK cell exhaustion is attributed to increased expression of immune checkpoints and decreased production of proliferative cytokines by these cells, immune checkpoint-targeted delivery of proliferative cytokines might induce robust and sustained antitumor immune responses. Here, the expression profile of NKG2A was first found to be narrower than that of PD-1 in tumor-infiltrated immune cells. Moreover, unlike PD-1, NKG2A was predominantly co-expressed with IL-2Rβγ in tumor-infiltrated CD8⁺ T and NK cells, but not in Tregs, suggesting that NKG2A might be an ideal target for delivery of IL-2Rβγ agonists to overcome T and NK exhausting. For NKG2A-targeted delivery of an IL-2Rβγ agonist, a single molecule of de novo designed N215 endowed with Immunoglobin G(IgG)-binding ability was coupled to an antibody against NKG2A (αNKG2A) to produce αNKG2A-N215. NKG2A- and IL-2Rβγ-binding were well preserved in αNKG2A-N215, allowing αNKG2A-N215 to act as both an immune checkpoint inhibitor and a T and NK cell stimulator. Intravenously injected αNKG2A-N215 predominantly induced expansion of tumor-infiltrated CD8⁺ T and NK cells while showing little stimulation of Tregs. Compared with the separate combination using αNKG2A and N215, αNKG2A-N215 exerted a greater antitumor effect in mice bearing MC38 or B16/F1 tumors. 50% of mice bearing MC38 tumors were cured by αNKG2A-N215, and long-term immunological memory against the tumor was induced in these mice. These results indicate that NKG2A is another ideal target for delivery of an IL-2Rβγ agonist, and αNKG2A-N215, with specificities for both NKG2A and IL-2Rβγ, might be developed as a novel agent for immunotherapy.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2482195"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the efficacy and constraints of platinum nanoparticles as adjuvant therapy in silicosis management.","authors":"Ge Ban, Yuanjie Chen, Yingbing Liang, Xiaona Wang, Dan Ding, Rui Liu, Jingjing Jia, Ran Zhao, Chenxia Wang, Na Li","doi":"10.1080/10717544.2024.2445257","DOIUrl":"10.1080/10717544.2024.2445257","url":null,"abstract":"<p><p>Silicosis represents a formidable occupational lung pathology precipitated by the pulmonary assimilation of respirable crystalline silica particulates. This condition engenders a cascade of cellular oxidative stress via the activation of bioavailable silica, culminating in the generation of reactive oxygen species (ROS). Such oxidative mechanisms lead to irrevocable pulmonary impairment. Contemporary scholarly examinations have underscored the substantial antioxidative efficacy of platinum nanoparticles (PtNPs), postulating their utility as an adjunct therapeutic modality in silicosis management. The physicochemical interaction between PtNPs and silica demonstrates a propensity for adsorption, thereby facilitating the amelioration and subsequent pulmonary clearance of silica aggregates. In addition to their detoxifying attributes, PtNPs exhibit pronounced anti-inflammatory and antioxidative activities, which can neutralize ROS and inhibit macrophage-mediated inflammatory processes. Such attributes are instrumental in attenuating inflammatory responses and forestalling subsequent lung tissue damage. This discourse delineates the interplay between ROS and PtNPs, the pathogenesis of silicosis and its progression to pulmonary fibrosis, and critically evaluates the potential adjunct role of PtNPs in the therapeutic landscape of silicosis, alongside a contemplation of the inherent limitations associated with PtNPs application in this context.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2445257"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning-assisted design of immunomodulatory lipid nanoparticles for delivery of mRNA to repolarize hyperactivated microglia.","authors":"Mehrnoosh Rafiei, Akbar Shojaei, Ying Chau","doi":"10.1080/10717544.2025.2465909","DOIUrl":"10.1080/10717544.2025.2465909","url":null,"abstract":"<p><p>Regulating inflammatory microglia presents a promising strategy for treating neurodegenerative and autoimmune disorders, yet effective therapeutic agents delivery to these cells remains a challenge. This study investigates modified lipid nanoparticles (LNP) for mRNA delivery to hyperactivated microglia, particularly those with pro-inflammatory characteristics, utilizing supervised machine learning (ML) classifiers. We developed and screened a library of 216 LNP formulations with varying lipid compositions, N/P ratios, and hyaluronic acid (HA) modifications. The transfection efficiency of eGFP mRNA was assessed in the BV-2 murine microglia cell line under different immunological states, including resting and activated conditions (LPS-activated and IL4/IL13-activated). ML-guided morphometric analysis tracked the phenotypes of various microglia subtypes before and after transfection. Four supervised ML classifiers were investigated to predict transfection efficiency and phenotypic changes based on LNP design parameters. The Multi-Layer Perceptron (MLP) neural network emerged as the best-performing model, achieving weighted F1-scores ≥0.8. While it accurately predicted responses from LPS-activated and resting cells, it struggled with IL4/IL13-activated cells. The MLP model was validated by predicting the performance of four unseen LNP formulations delivering eGFP mRNA to LPS-activated BV2 cells. HA-LNP2 emerged as optimal formulation for delivering target IL10 mRNA, effectively suppressing inflammatory phenotypes, evidenced by shifts in cell morphology, increased IL10 expression, and reduced TNF-α levels. We also evaluated HA-LNP2 on LPS-activated human iPSC-derived microglia, confirming its efficacy in modulating inflammatory responses. This study highlights the potential of tailored LNP design and ML techniques to enhance mRNA therapy for neuroinflammatory disorders by leveraging carrier's immunogenic properties to modulate microglial responses.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2465909"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}