Drug Delivery最新文献

{"title":"Lysosome-directed targeted protein degradation technologies for overcoming cancer drug resistance: mechanisms, design principles, and therapeutic opportunities.","authors":"Huixin Mao, Ying Zhang, Mingqi Liu, Yao Yao, Yujie Peng, Xuwei Zhou, Hao Huang, Weidong Fei, Caihong Zheng, Yiqing Ye","doi":"10.1080/10717544.2026.2679844","DOIUrl":"10.1080/10717544.2026.2679844","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy to address cancer drug resistance by enabling the selective and efficient degradation of disease-associated proteins through cellular mechanisms. Since 2020, lysosome-targeting chimeras (LYTACs) have gained attention for expanding targeted protein degradation to extracellular and membrane-associated disease-related proteins beyond the reach of proteolysis-targeting chimeras (PROTACs). In practice, LYTACs can overcome resistance by degrading instead of inhibiting them. This efficient and durable removal of resistance-associated drivers thereby suppresses compensatory signaling, restores drug sensitivity, and contributes to remodeling the tumor microenvironment. To facilitate the clinical translation of this emerging technology, this review systematically compares the mechanistic and functional advantages of LYTACs over PROTACs, summarizes key design principles, and categorizes major LYTAC modalities, including AbTACs, MoDE-As, and nano-LYTACs. We further discuss their <i>in vivo</i> pharmacological behaviors, with particular emphasis on stability, tumor selectivity, and degradation efficiency. Importantly, this article comprehensively highlights recent advances in the application of LYTACs for overcoming therapeutic resistance, including resistance to chemotherapy, targeted therapy, and immunotherapy. Finally, current translational bottlenecks, such as delivery efficiency, receptor heterogeneity, and pharmacokinetic limitations, are critically analyzed. Collectively, while still in its early stages of development, LYTAC-based lysosomal degradation represents a promising, paradigm-shifting strategy for targeting previously intractable mechanisms of cancer resistance.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2679844"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148041643","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":"Analyzing the impact of subcutaneous injection needle, device, and administration characteristics on patient pain, anxiety, and safety: a systematic literature review.","authors":"Mehul Desai, Keith Candiotti, Aaron Pinkhasov, R Brandon Hunter, Harman Chopra, Lisa Gorski, Samantha Shenoy","doi":"10.1080/10717544.2026.2719057","DOIUrl":"10.1080/10717544.2026.2719057","url":null,"abstract":"<p><p>The subcutaneous (SC) injection route is a commonly used and important method for therapeutic delivery of a wide range of compounds, and needle characteristics have a significant influence on patient pain, anxiety, safety, and other outcomes. This systematic review evaluates the evidence on how needle-specific characteristics (e.g. gauge, length, tip design, wall thickness, concealment) and administration- or device-related factors can affect patient-reported outcomes and clinical safety indicators during and following SC injections. A comprehensive search was conducted in MEDLINE, PubMed, Embase, and ClinicalTrials.gov in June 2024. Studies were included if they assessed the relationship between needle characteristics and pain, anxiety, safety, or related outcomes in individuals receiving SC injections. A dual-reviewer process was used for study selection, data extraction, and quality assessment. Sixty-two studies met inclusion criteria. Evidence consistently indicated that thinner and shorter needles reduced patient-reported pain and adverse events such as bruising and bleeding. Tapered and lubricated needles, hidden or retractable needle designs, and use of autoinjectors or prefilled syringes also contributed to reduced anxiety and improved user satisfaction. However, results were heterogeneous, and many studies lacked sufficient power or single-variable evaluation of individual needle parameters, limiting definitive conclusions. Needle characteristics significantly influence patient experience and safety with SC delivery. While both clinical evidence and practical experience clearly favor thinner, shorter, and concealed needles, further standardized, high-quality research is needed to isolate and quantify the specific contributions of individual needle characteristics to optimize injection practices and support patient-centered device design.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2719057"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148826437","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":"Overcoming the blood‒brain barrier: nanomedicine strategies for targeted delivery and multimodal therapy in Alzheimer's disease.","authors":"Jiahui Li, Liting Guo, Weiyi Cai, Juanjuan Mei, Jie Liu, Yanan Liu","doi":"10.1080/10717544.2026.2645830","DOIUrl":"10.1080/10717544.2026.2645830","url":null,"abstract":"<p><p>Alzheimer's disease (AD) remains a significant therapeutic challenge, primarily because the formidable blood‒brain barrier (BBB), which drastically limits the brain bioavailability of most drugs. Nanoparticle-based drug delivery systems offer a promising strategy to overcome this central obstacle. This review systematically examines the design, mechanisms, and applications of nanomedicine in AD therapy. We analyze key strategies for enhancing BBB penetration through surface engineering and the utilization of various nanocarriers, including liposomes, exosomes, dendrimers, and carbon dots. Furthermore, we discuss how stimuli-responsive release mechanisms (e.g. responsive to pH, enzymes, reactive oxygen species, light, or ultrasound) enable targeted and precise drug delivery. A critical focus is placed on how these multifunctional nanoplatforms can address multiple AD pathogenic pathways simultaneously, such as amyloid-β and tau aggregation, cholinergic dysfunction, oxidative stress, neuroinflammation, and gut‒brain axis dysregulation. Although preclinical evidence is compelling, the clinical translation of these nanotherapies is hindered by challenges related to long-term biocompatibility, scalable manufacturing, patient heterogeneity, and regulatory frameworks. This review highlights the translational potential of nanomedicine in AD treatment while outlining the key hurdles that must be addressed for its successful implementation.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2645830"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491014","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":"Oral self-assembly nanoemulsion drives <i>in vivo</i> hepatic stellate cell-targeting drug delivery in liver fibrosis.","authors":"Xinjing Shen, Jie Deng, Aijiao Jiang, Qianqi Cai, Deyong Tian, Linlin Zhao, Jing Ye, Lie Zhang, Yucheng Xiang, Quan Zhang","doi":"10.1080/10717544.2026.2686514","DOIUrl":"10.1080/10717544.2026.2686514","url":null,"abstract":"<p><p>Hepatic fibrosis is a chronic liver disease that requires long-term treatment and is characterized by the excessive accumulation of extracellular matrix (ECM), which is produced primarily by activated hepatic stellate cells (aHSCs). Oral medication represents a non-invasive and crucial strategy for prolonged therapy. However, achieving targeted drug delivery to aHSCs through oral administration remains a significant challenge because of the susceptibility of nanoparticles to structural disruption during intestinal transit. To address this, an oral vitamin A (VA)-functionalized self-nanoemulsifying drug delivery system (termed VA-SNEDDS) was fabricated for the precise delivery of morin (MOR) to aHSCs for the treatment of liver fibrosis. After oral administration, the designed VA-SNEDDS successfully translocated across the intestinal epithelium while maintaining the structural integrity of the nanoemulsion, entered the systemic circulation <i>via</i> the lymphatic pathway, and ultimately accumulated in aHSCs within fibrotic livers through VA- and retinol-binding protein receptor-mediated binding. In a carbon tetrachloride (CCl₄)-induced fibrotic rat model, treatment with MOR-loaded VA-SNEDDS significantly attenuated liver fibrosis by reducing ECM deposition, hydroxyproline content, and transforming growth factor-β1 (TGF-β1) expression while concurrently restoring liver function. This study provides an orally administrable aHSCs-targeted platform with high translocation efficiency and indicates potential for this strategy in the treatment of liver fibrosis.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2686514"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239068","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":"Statement of retraction: insulin-loaded PLGA microspheres for glucose-responsive release.","authors":"","doi":"10.1080/10717544.2025.2604934","DOIUrl":"10.1080/10717544.2025.2604934","url":null,"abstract":"","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2604934"},"PeriodicalIF":8.1,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12720671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780525","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":"Folate-targeted gold nanoparticles for doxorubicin delivery in tumor spheroids.","authors":"Raffaella Daniele, Agnese Fragassi, Cristiano Pesce, Francesco Tognetti, Marco Verona, Giovanni Marzaro, Stefano Salmaso, Paolo Caliceti","doi":"10.1080/10717544.2025.2607390","DOIUrl":"10.1080/10717544.2025.2607390","url":null,"abstract":"<p><p>Targeted drug delivery systems represent a promising strategy for enhancing the efficacy and specificity of cancer therapy. In this study, 35 nm folate-targeted gold nanoparticles are presented as nanoparticle-drug conjugates obtained by anchoring on their surface lipoyl terminating doxorubicin prodrug (proDoxo) releasable at the endolysosomal acidic pH to prevent off-site toxic effects. Colloidal stable nanoparticles with a density of proDoxo up to 1000 molecules/particle and 2 kDa mPEG-SH coating were obtained. At pH 5, Doxo was completely released from the nanoparticles in 5 days while only 13% was released over the same period at pH 7.4. The nanoparticle decoration with folic acid as a targeting agent bestowed nanosystems with selective drug delivery to folate receptor (FR)-overexpressing cancer cells and controlled intracellular release. This led to enhanced cancer cell killing by folated nanoparticles compared to their nontargeted counterparts. Moreover, folated nanoparticles were found to distribute more homogeneously inside KB^FR+ cancer cell spheroids than non-targeted nanoparticles, resulting in higher spheroid volume reduction.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2607390"},"PeriodicalIF":8.1,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12777817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145855048","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":"Development and evaluation of alginate-based gastroretentive raft-forming systems enabling sustained release of propolis in gastric ulcer treatment.","authors":"Haniye Takbirgou, Maryam Salami, Gholamreza Askari, Zahra Emam-Djomeh, Raimar Löbenberg, Michael J Serpe, Neal M Davies, Wing-Fu Lai","doi":"10.1080/10717544.2026.2616887","DOIUrl":"10.1080/10717544.2026.2616887","url":null,"abstract":"<p><p>This study aimed to develop alginate-based raft-forming systems incorporating propolis-whey protein isolate (5%) nanocomplexes to alleviate reflux symptoms and enable the sustained, gastric-specific delivery of propolis for ulcer management. Propolis-protein complexes were prepared at four ratios (2.5:100, 5:100, 7.5:100, and 10:100 w/v) by heating at 85 °C for 5 h at pH 2, producing nanofibrils characterized by thioflavin T fluorescence, intrinsic fluorescence, encapsulation efficiency (up to 78%), and antioxidant activity. The optimal complex was incorporated into alginate rafts at 5%, 10%, and 15% (w/v). Rafts exhibited prolonged floatability (>8 h), increased thickness (from 3.2 ± 0.4 mm to 4.7 ± 0.3 mm with higher propolis loading), enhanced mechanical strength (up to 1.6-fold improvement), and improved reflux resistance. SEM imaging revealed a more compact and uniform porous structure, while FT-IR confirmed molecular interactions between alginate and the propolis-protein complex. <i>In vitro</i> release studies in simulated gastric fluid showed suppression of initial burst release, with sustained propolis release over 6-8 h. Overall, alginate rafts containing propolis-protein nanocomplexes demonstrated enhanced structural performance, controlled release behavior, and promising potential for targeted gastric delivery in the management of gastric ulcers.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2616887"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12829413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017945","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":"Targeted proteoform degradation for precision drug design, delivery, and therapy.","authors":"Chenyu Cui, Haoyue Zhang, Xinmiao Wang, Na Li, Xianquan Zhan","doi":"10.1080/10717544.2026.2665871","DOIUrl":"10.1080/10717544.2026.2665871","url":null,"abstract":"<p><p>Ubiquitin-proteasome system (UPS)-mediated targeted protein degradation (TPD) is a central mechanism of maintaining protein homeostasis, which is closely associated with multiple diseases. Proteolysis-targeting chimeras (PROTACs) represent a major platform in TPD research and have demonstrated advantages relative to traditional intervention methods, such as small-molecule inhibitors, particularly in expanding the scope of targetable proteins. PROTACs have significant scientific merits in drug discovery and development. Currently, TPD still focuses on the conventional 'protein' level. However, the development of proteoform and proteoformics has enriched the deep understanding of the structural and functional diversities of a conventional protein. Targeted proteoform degradation (TPfD) has been proposed as an approach to more accurately recognize subtle structural and functional alterations within canonical proteins, thereby potentially improving precision drug delivery. Pathology-specific proteoform-based TPfD may facilitate the design of more precisely targetable degradation tools, potentially shifting strategies from general targeting toward more refined clearance. This review discusses the concept, mechanism, and developmental landscape of protein-based TPD and its core tool PROTACs, while systematically elaborating on the limitations of traditional TPD technologies - particularly the challenges associated with distinguishing functionally heterogeneous proteoforms. Thus, this review proposes the innovative concept of proteoform-based TPfD, detailing its technical foundations (rooted in proteoformics), core design methodologies (including ligand optimization, linker system engineering, and E3 ligase selection), and key applications in disease molecular typing, personalized drug development, and dynamic therapeutic regimen optimization. It further explores the potential role of TPfD in advancing precision medicine and discusses how proteoform-oriented strategies may contribute to refining therapeutic approaches for complex diseases.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2665871"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13159605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834889","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":"Comparative safety profiles of antibody-drug conjugates: a real-world analysis of monotherapy and combination regimens in solid tumors.","authors":"Linjie Fan, Yuze Yin, Wei Zhuang, Danming He, Rui Wan, Boyang Sun, Hua Bai, Jie Wang","doi":"10.1080/10717544.2026.2712694","DOIUrl":"10.1080/10717544.2026.2712694","url":null,"abstract":"<p><p>The expanding clinical use of Antibody-Drug Conjugates (ADCs) necessitates a clearer understanding of their real-world toxicity profiles across diverse clinical settings. This retrospective pharmacovigilance study analyzed 19,697 adverse event (AE) reports for seven approved ADCs from the FDA Adverse Event Reporting System (FAERS) database (Q1 2004 to Q1 2025). Using disproportionality analysis validated by multivariable logistic regression, we identified safety signals for both monotherapy and combination regimens. The analysis revealed that toxicity profiles are strongly driven by an ADC's molecular structure and treatment setting. Target-specific 'on-target, off-tumor' effects were prominent, linking Nectin cell adhesion molecule 4 (NECTIN-4) targeting to skin reactions, Trophoblast cell-surface antigen 2 (TROP2) to gastrointestinal toxicities, and both folate receptor <i>α</i> (FRα) and tissue factor (TF) to ocular disorders. Furthermore, payload and linker types drove distinct toxicities; topoisomerase I inhibitors were associated with increased respiratory toxicity and mortality, while non-cleavable linkers conferred a significantly stronger risk of hepatobiliary toxicity. Combination regimens not only amplified specific risks, such as endocrine disorders with immune checkpoint inhibitors (ICIs), but also fundamentally reshaped toxicity kinetics, accelerating AE onset with ICIs while significantly delaying it with other combinations. This real-world analysis confirms that ADC toxicities are highly specific to their molecular design and clinical context, highlighting that understanding these complex structural and kinetic interplays is essential for optimizing safety management in clinical practice.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2712694"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677596","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":"Artificial intelligence and extracellular vesicles in oncology: towards tumor diagnosis, prediction, and therapy.","authors":"Xiangyu Li, Hao Su, Yaping Li, Longyang Jiang, Jie Zhou, Liaoyun Zhang, Yilan Huang, Xuping Yang, Min Li","doi":"10.1080/10717544.2026.2713415","DOIUrl":"10.1080/10717544.2026.2713415","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) have emerged as promising tools for early cancer detection, therapeutic monitoring, and drug delivery in oncology. Artificial intelligence (AI), particularly machine learning and deep learning, offers new analytical tools and computational approaches for EV research. This review summarizes recent advances in the application of AI to EV isolation, characterization, diagnosis, and drug delivery, with particular emphasis on its potential to enhance tumor detection sensitivity, diagnostic accuracy, and the rational design of delivery platforms. Special attention is given to the roles and recent applications of AI models in integrating multimodal features, characterizing EV heterogeneity, supporting diagnostic classification, and modeling in vivo behavior. Moreover, we examine the integration of AI with EV-based microfluidic isolation, surface-enhanced Raman spectroscopy (SERS), fluorescence imaging, and multiomics analysis. Among these areas, AI-assisted EV diagnostic applications are comparatively closer to clinical translation, with several studies incorporating patient-derived samples and AI-assisted diagnostic platforms, whereas AI-guided therapeutic EV design strategies remain largely exploratory. With the continued accumulation of multicenter, cross-platform EV datasets, improvements in algorithmic robustness, and closer integration of computational and experimental workflows, AI may support further clinical evaluation of EV-based diagnostics and the systematic optimization of therapeutic EV platforms.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2713415"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148724484","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}