bims-engexo 2026-07-12 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–07–12
twelve papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineered Exosomes for Skin Antiaging: A New Frontier in Regenerative Medicine.
Breaking the vicious cycle of impaired angiogenesis and chronic inflammation in diabetic wounds: a bioengineered microneedle system delivering RGD-modified M2 exosomes.
Engineered exosomes deliver structurally optimized toad BAX to reactivate mitochondrial apoptosis in colorectal cancer.
Engineered extracellular vesicles for drug delivery in hepatocellular carcinoma.
Engineered exosomes encapsulated miR-218-5p alleviate the progression of PM2.5-induced epithelial-mesenchymal transition via ferroptosis pathway.
Photoreceptor-targeted engineered exosomes encapsulating black phosphorus quantum dots for alleviating photoreceptor degeneration.
Extracellular vesicles derived from engineered BMSCs improve damaged cartilage in mice with osteoarthritis by delivering PBX1.
Nature-derived exosome-like nanoparticles (NELNs) for intracellular transport and targeted RNA delivery.
Engineering EVs Via ZnBGs-Integrated 3D Dynamic Culture for Type II Diabetic Pressure Ulcer Therapy.
Optimizing miRNA Loading into Platelet Exosomes via Electroporation: A Comparative Analysis of Buffer Systems and Voltage Parameters for Enhanced Targeted Drug Delivery.
Engineered Red Blood Cell-Derived Extracellular Vesicles With Klotho Peptide Protect the Kidney From Fibrosis.
Brain targeting and trafficking of extracellular vesicles in central nervous system diseases: a therapeutic roadmap.

FASEB J. 2026 Jul 15. 40(13): e72056

Engineered Exosomes for Skin Antiaging: A New Frontier in Regenerative Medicine.

YiDi Sun, XinYue Guo, ZiXue He, YaXuan Cui, Dezhong Wen, Baigong Xue, LiSha Li.

  Skin aging is an intricate and multidimensional biological process driven by both endogenous and exogenous factors. It manifests as impaired skin structure and function, morphological alterations, and an elevated risk of associated disorders. Current skin antiaging therapies have made considerable advancements. However, notable challenges persist regarding safety, long-term efficacy, and delivery efficiency. These challenges have prompted the field of regenerative medicine to pursue more effective therapeutic strategies. Engineered exosomes (Exos) are nanoscale vesicles optimized through bioengineered strategies. They exhibit excellent biocompatibility, low immunogenicity, and a strong capability to deliver diverse bioactive molecules. Stem cell-derived exosomes (SC-Exos) represent ideal sources for engineered Exos. However, natural Exos are limited by low yield, insufficient drug-loading capacity, and poor targeting efficiency. To address these limitations, engineered strategies have been developed to enhance yield, enrich functional components, and achieve targeted delivery. Furthermore, this review investigates the combined use of engineered Exos with delivery systems such as microneedles and gels to enhance therapeutic efficacy. Ongoing technological advancements have enabled engineered Exos to emerge as a safe, efficient, precise, and promising frontier in precision skin antiaging. They are poised to drive revolutionary breakthroughs in regenerative medicine.

Keywords:  engineered exosomes; exosomes; regenerative medicine; skin aging

DOI:  https://doi.org/10.1096/fj.202601698R
Burns Trauma. 2026 ;14 tkag013

Breaking the vicious cycle of impaired angiogenesis and chronic inflammation in diabetic wounds: a bioengineered microneedle system delivering RGD-modified M2 exosomes.

HongYu Wang, BaoHua Wei, BaiShi Wang, Mi Chai, Jing Ren, Yan Han, LingLi Guo.

   Background: Persistent local tissue hypoperfusion and chronic inflammation are central challenges in diabetic wound management. The development of effective therapeutic strategies to mitigate prolonged inflammation and enhance tissue vascularization is crucial for accelerating diabetic wound healing. This study aimed to develop soluble microneedle materials that simultaneously target both aspects to improve the clinical prognosis of diabetic wounds.
Methods: A stable macrophage cell line overexpressing basic fibroblast growth factor (bFGF) was established using lentiviral transfection. After M2 polarization was induced with interleukin-4 (IL-4) and IL-10, exosomes were isolated via ultracentrifugation and surface-functionalized with arginine-glycine-aspartic acid (RGD)-targeting peptides. The reparative effects of these exosomes on human umbilical vein endothelial cells (HUVECs) with high glucose-induced injury were evaluated using scratch test, 5-ethynyl-2'-deoxyuridine (EdU) staining, and cell counting kit-8 assays. A delivery system based on soluble hyaluronic acid microneedles (MNs) loaded with engineered exosomes was then developed. Its therapeutic efficacy was evaluated in a diabetic wound mouse model, and the underlying mechanisms were explored via ribonucleic acid (RNA) sequencing.
Results: Targeted engineered exosomes (TE-Exos) derived from bFGF-overexpressing M2 macrophages with surface RGD modification were successfully prepared. Assays revealed that TE-Exos exhibited specific targeting to HUVECs with high glucose-induced injury and significantly enhanced cellular proliferation, migration, and tube formation. Furthermore, the polarization ratio of macrophages improved after TE-Exos treatment. In vivo, the MN-mediated delivery of TE-Exos markedly accelerated diabetic wound healing by enhancing re-epithelialization, collagen deposition, and angiogenesis. Furthermore, the treatment modulated the wound microenvironment by reducing the infiltration of proinflammatory M1 macrophages while increasing the proportion of reparative M2 macrophages. RNA sequencing analysis indicated that the therapeutic effects were mediated primarily through the inhibition of excessive inflammation and the activation of angiogenesis-related signaling pathways.
Conclusions: This innovative strategy breaks the vicious cycle of impaired angiogenesis and chronic inflammation in diabetic wounds through a synergistic mechanism involving 'angiogenesis, inflammation regulation, and precise delivery'. The combination of targeted exosome engineering with an MN delivery system not only overcomes the limitations of conventional growth factor therapies but also enables intelligent modulation of the wound microenvironment, offering novel theoretical insights and practical approaches for clinical translation.

Keywords:  Diabetic wounds; Macrophage polarization; Microneedles; Targeted engineered exosomes; Wound healing

DOI:  https://doi.org/10.1093/burnst/tkag013
Front Oncol. 2026 ;16 1882315

Engineered exosomes deliver structurally optimized toad BAX to reactivate mitochondrial apoptosis in colorectal cancer.

Xinqiang Xu, Hongjie Wu, Yixin Yan, Hongwei Cui, Tianyi Yu, Ye Yang, Zhendong Deng, Jinjun Qian.

   Introduction: Mitochondrial apoptosis evasion, driven by overexpression of anti-apoptotic BCL-2 family proteins, remains a major obstacle in the effective treatment of colorectal cancer (CRC). While BCL-2 homology 3 (BH3) mimetics (such as venetoclax) have shown clinical efficacy in hematologic malignancies, their effectiveness in solid tumors is limited. Direct delivery of pro-apoptotic effectors, including BAX, offers an alternative strategy; yet, the therapeutic potential of non-human BAX orthologs and their delivery methods has not been explored.
Methods: The functional activity of Xenopus laevis (African clawed frog) BAX was evaluated in human CRC cell lines (HCT116, LOVO) and in cell line-derived xenograft (CDX) and AOM/DSS-induced CRC mouse models. Direct binding to human BCL-2 was quantified by microscale thermophoresis. The mechanism of action was elucidated via JC-10 staining, subcellular fractionation and liposome permeabilization assays.Structure-guided mutagenesis based on the BCL-2-Beclin-1 BH3 complex (PDB: 5VAU) was employed to generate a triple mutant (I86T, A102S, R109M) . Optimized BAX was packaged into engineered exosomes for targeted delivery, and their anti-tumor efficacy and safety were assessed in CDX, patient-derived xenograft (PDX), and AOM/DSS models.
Results: Toad BAX directly bound human BCL-2 (Kd = 12.7 ± 1.9 µM), triggered mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, and caspase-9/3 activation, thereby suppressing CRC cell proliferation and inducing apoptosis. The rationally designed triple mutant exhibited enhanced BCL-2 affinity and superior in vivo antitumor activity compared to wild-type toad BAX. Exosome-mediated delivery of the optimized BAX efficiently targeted CRC cells, inhibited tumor growth in PDX models, and extended overall survival in AOM/DSS-induced CRC without inducing overt toxicity.
Discussion: This study establishes structurally optimized cross-species BAX, delivered via engineered exosomes, as a potent and safe strategy to reactivate mitochondrial apoptosis against CRC. It provides a preclinical foundation for protein-based therapeutics targeting apoptosis-evasive solid tumors, offering a mechanistically distinct alternative to conventional BH3 mimetics.

Keywords:  BAX; BCL2; colorectal cancer; mitochondrial apoptosis; structural optimization; targeted delivery

DOI:  https://doi.org/10.3389/fonc.2026.1882315
Int J Pharm. 2026 Jul 08. pii: S0378-5173(26)00610-1. [Epub ahead of print]701 127162

Engineered extracellular vesicles for drug delivery in hepatocellular carcinoma.

Caiyun Zhang, Junjie Ni, Can Zhang, Weihong Long, Xingyue Wang, Jing Shen, Xu Wu, Mingxing Li, Fukuan Du, Yu Chen, Shuai Deng, Yueshui Zhao, Zhuo Chen, Xi He, Xiaobing Li, Zhangang Xiao.

  The high heterogeneity and immunosuppressive microenvironment of hepatocellular carcinoma (HCC) pose significant challenges to existing therapies. Extracellular vesicles (EVs) are natural nanocarriers with relatively low immunogenicity and intrinsic barrier-crossing capabilities, and they show potential as HCC biomarkers and therapeutic delivery vehicles. However, their clinical utility is severely hindered by low drug loading efficiency, poor targeting specificity, and a lack of scalable and standardized manufacturing protocols. This review briefly outlines the fundamental roles of EVs in HCC diagnosis, prognosis, and therapy, and then focuses on engineering strategies designed to overcome these inherent limitations. Furthermore, it critically evaluates the opportunities and barriers to the clinical translation of EV-based therapies for HCC, aiming to provide a translational framework for developing EVs into next-generation precision medicine platforms for HCC. This review integrates bioengineering advances with regulatory and clinical translation considerations. The available evidence suggests that the clinical future of engineered EVs depends less on maximal multifunctionality and more on scalable manufacturing, reproducible quality control, and clearly defined therapeutic mechanisms.

Keywords:  5-Fluorouracil; Cannabidiol; Clinical translation; Cypate; Doxorubicin; Drug delivery; Erastin; Extracellular vesicles; Hepatocellular carcinoma; Lenvatinib; Nanotechnology; Norcantharidin; Rapamycin; Rose Bengal; Sorafenib; Tissue engineering

DOI:  https://doi.org/10.1016/j.ijpharm.2026.127162
Redox Biol. 2026 Jul 06. pii: S2213-2317(26)00289-2. [Epub ahead of print]95 104290

Engineered exosomes encapsulated miR-218-5p alleviate the progression of PM2.5-induced epithelial-mesenchymal transition via ferroptosis pathway.

Lili Shi, Juan Wang, Hao Liu, Chen Ge, Wenyuan Zhu, Fengyun Chi, Tianao Ling, Zhaohui Hu, Dongbo Zhang, Qingping Liu, Ze Yang, Yaxian Pang, Yujie Niu, Lei Bao, Rong Zhang.

  Air pollution represents the greatest global environmental risk to human health, particularly regarding pulmonary fibrosis. Among atmospheric pollutants, airborne fine particulate matter (PM2.5) contributes most significantly to global mortality and disease burden. The epithelial-mesenchymal transition (EMT) constitutes a critical process in PM2.5-induced pulmonary fibrosis, concomitant with iron deposition and disrupted lipid peroxide metabolism. We found that PM2.5-induced ferroptosis contributes to EMT in lung tissue of mice after PM2.5 exposure. An in vitro macrophage-epithelial cell co-culture model demonstrated that exosomes from PM2.5-exposed macrophage induced ferroptosis, thereby driving EMT in epithelial cells. Pharmacological inhibition of the HO-1, which is involved in ferroptosis regulation significantly reversed the EMT alterations. Crucially, miR-218-5p was identified as a potential macrophage-derived exosomal miRNA targeting HO-1 to mediate ferroptosis-driven EMT in epithelial cells. Furthermore, engineered exosomes encapsulating miR-218-5p were constructed and administered via nebulization to alleviate PM2.5-induced pulmonary fibrosis in mice. In summary, this work provides experimental evidence supporting a targeted delivery strategy against PM2.5-induced pulmonary fibrosis.

Keywords:  EMT; Exosome engineering; Ferroptosis; PM(2.5); Pulmonary fibrosis

DOI:  https://doi.org/10.1016/j.redox.2026.104290
J Nanobiotechnology. 2026 Jul 08.

Photoreceptor-targeted engineered exosomes encapsulating black phosphorus quantum dots for alleviating photoreceptor degeneration.

Jia Liang, Xiangqing Hei, Lu Chen, Zhenhua Zou, Yuke Ji, Lujia Feng, Wangting Li, Yijing Zhuang, Bingyu Bai, Renxue Liang, Yunyun Zou, Pan Xiao, Qiang Lin, Huiyan Zheng, Dong Fang, Wei Chi, Shaochong Zhang.

  Photoreceptor degeneration is a major cause of irreversible visual impairment worldwide, most notably in retinitis pigmentosa (RP). Here, we developed a dual-targeted therapeutic nanoplatform by loading black phosphorus quantum dots (BPQDs) into human dental pulp mesenchymal stem cell-derived exosomes (hDPSC-Exos) and surface-modifying with cell-penetrating peptide transactivated transcription (TAT) and photoreceptor-specific peptide MH42, namely TAT/MH42-engineered black phosphorus quantum dot-loaded exosomes (M/T-BPQD@Exos). M/T-BPQD@Exos showed typical exosomal morphology and good uniformity. In vitro, M/T-BPQD@Exos effectively protected 661 W photoreceptor cells against N-methyl-N-nitrosourea (MNU) injury. In vivo, M/T-BPQD@Exos specifically accumulated in the outer nuclear layer (ONL) and significantly preserved retinal structure and visual function in MNU-induced photoreceptor degeneration rats. Biosafety assessment confirmed no obvious systemic toxicity and inflammation. Mechanistically, M/T-BPQD@Exos alleviated calcium overload, maintained mitochondrial integrity, and suppressed mitochondrial apoptosis by regulating Bcl-2, Bax, and cleaved caspase-3. This study provides a safe and precise strategy for photoreceptor protection in retinal degenerative diseases.

Keywords:  Black phosphorus quantum dots; Exosome; Mitochondrial apoptosis; Photoreceptor degeneration; Targeted delivery

DOI:  https://doi.org/10.1186/s12951-026-04763-x
Stem Cell Res Ther. 2026 Jul 10.

Extracellular vesicles derived from engineered BMSCs improve damaged cartilage in mice with osteoarthritis by delivering PBX1.

Yunqi Zhang, Fusen Wang, Huan Yu, Changqing Jiang, Zhong Li, Rongqiang Bu, Jun Yu.

   BACKGROUND: The beneficial effects of bone marrow mesenchymal stem cells (BMSCs) have been linked to their secreted extracellular vesicles (EVs). These EVs can suppress cartilage degradation and prevent apoptosis in articular cells. We aimed to explore the therapeutic efficacy of engineered BMSCs-EVs in the treatment of osteoarthritis (OA).
METHODS: The isolation of BMSC-derived EVs was conducted via ultracentrifugation techniques, followed by characterization. Engineered EVs were obtained by transfecting chondrocyte-affinity peptide (CAP) and Pre-B-cell leukemia transcription factor 1 (PBX1) expression plasmids into BMSCs. OA injury was induced by the treatment of chondrocytes with IL-1β, and the OA mouse model was established by DMM surgery. The efficacy of different EVs was examined in vitro and in vivo. EVs treatment and combined genetic interventions were performed in vitro and in vivo.
RESULTS: Both CAP modification and increased protein loading of PBX1 strengthened the protective effect of EVs on chondrocytes and ameliorated OA-induced cartilage damage. PBX1 promoted extracellular signal-regulated kinase (ERK) signaling and the expression of the downstream molecule c-FOS in chondrocytes by activating the transcriptional expression of calcium channel voltage-dependent subunit beta 4 (CACNB4). The chondroprotective effect of engineered EVs was significantly attenuated by inhibiting CACNB4/ERK signaling in IL-1β-treated chondrocytes, as well as in the DMM-induced mouse model.
CONCLUSION: Engineering (CAP modification and increased PBX1 protein loading) enhances the therapeutic efficacy of BMSCs-EVs on chondrocytes, which depends on the activation of the CACNB4/ERK signaling. Engineered EVs represent a promising treatment for OA cartilage damage.

Keywords:  CACNB4; Cartilage damage; Engineered extracellular vesicles; Osteoarthritis; PBX1

DOI:  https://doi.org/10.1186/s13287-026-05152-9
Biotechnol Adv. 2026 Jul 08. pii: S0734-9750(26)00185-0. [Epub ahead of print]92 108979

Nature-derived exosome-like nanoparticles (NELNs) for intracellular transport and targeted RNA delivery.

Baoyu Xu, Hong Yang, Kang Chen, Leli Wang, Jianhua Fan, Hong Du, Wenzhong Guo, Roger Ruan, Xiaojun Yan, Yulong Yin, Pengfei Cheng.

  As exosomes serve as pivotal mediators of intercellular communication, research on exosomes has expanded markedly from its conventional focus on mammalian sources to the burgeoning field of nature-derived exosome-like nanoparticles (NELNs). Endowed with favorable biocompatibility, low immunogenicity, and wide, readily accessible sources, NELNs have emerged as promising delivery vehicles to address long-standing bottlenecks in RNA-based therapeutic delivery. However, their clinical translation is significantly impeded by the lack of a consensus definition and standardized manufacturing workflows. This review focuses on NELNs-mediated therapeutic RNA delivery; systematic delineation of NELNs' characteristics and biogenic pathways remains insufficient, and further investigation is warranted for details of NELNs' properties, including biochemical composition, inherent biological functions, in vivo biodistribution regulated by distinct administration routes, cellular uptake mechanisms, and regulatory pathways of targeted delivery, as well as state-of-the-art strategies for the construction and optimization of RNA-loaded NELNs. This review systematically characterizes the intracellular trafficking, cargo release kinetics, and metabolic degradation profiles of NELNs-RNA complexes, summarizes their therapeutic applications in brain disorders, intestinal diseases, and tumors, analyzes critical translational challenges including scalable production, batch-to-batch consistency, long-term safety, and targeting precision, and proposes rational optimization strategies to advance mechanistic research and clinical translation of NELNs-based RNA delivery systems.

Keywords:  Intracellular trafficking; Microalgae; Nature-derived exosome-like nanoparticles (NELNs); RNA-based therapeutics; Therapeutic RNA delivery

DOI:  https://doi.org/10.1016/j.biotechadv.2026.108979
Small. 2026 Jul 08. e74430

Engineering EVs Via ZnBGs-Integrated 3D Dynamic Culture for Type II Diabetic Pressure Ulcer Therapy.

Zhipeng Sun, Yilin Ding, Xiaolin Chen, Zilin Wu, Yue Huang, Huitong Luo, Xiaodong Cao.

  Pressure ulcers (PUs) under type II diabetic conditions pose a significant clinical challenge due to damage to the vascular and neural networks, a situation further complicated by sustained mechanical pressure resulting from prolonged patient immobility. While engineered extracellular vesicles (EVs) hold therapeutic potential, conventional production methods face limitations such as rapid drug inactivation, compromised EV structural integrity, and poor scalability. Metal-doped bioactive glass (mBGs) extract induces cellular phenotypic changes through continuous ion release and nanoparticle mineralization, employing a non-genetic, non-destructive approach that preserves the integrity of EVs and enables more stable, directed functional induction. To further facilitate scalable manufacturing without compromising directed functional induction, we coupled ZnBGs extract with 3D dynamic cell culture technology for enhanced EVs production. The resulting 3D-ZnBG-EVs significantly increased protein yield and demonstrated enhanced angiogenic and neurogenic functions, which are mediated via the PI3K-AKT-HIF-1α axis. In a Sprague-Dawley (SD) rat model of type II diabetic pressure ulcers, ZnBG-EVs significantly improved vascular and neural repair, extracellular matrix deposition, collagen maturation, and overall wound closure. This integrated strategy provides a scalable, function-directed platform for EVs-based PUs therapy.

Keywords:  3D dynamic cell culture; EVs; SCAPs; ZnBGs; type II diabetic pressure ulcers

DOI:  https://doi.org/10.1002/smll.74430
Mol Biotechnol. 2026 Jul 04.

Optimizing miRNA Loading into Platelet Exosomes via Electroporation: A Comparative Analysis of Buffer Systems and Voltage Parameters for Enhanced Targeted Drug Delivery.

Yuhan Wang, Yali Wang, Qiong Yuan, Zhi Cai, Ling Jiang, Fujiang Xu, Shan Hu.

  Exosomes, which transport miRNAs in vivo, hold significant therapeutic potential for treating diseases. Current methods for loading miRNAs into exosomes include sonication, co-incubation, kit-based transfection, and electroporation, with electroporation being the most efficient and widely used approach. However, standardized protocols for electroporation conditions remain lacking, necessitating the optimization of electroporation parameters to enhance the utility of extracellular vesicles as drug delivery vehicles in vivo. Platelets were isolated from healthy volunteer blood donors, and platelet-derived exosomes were extracted. The exosomes were labeled with specific dyes and loaded with miRNA using Bio-Rad Gene Pulser Electroporation buffer or 50 mM trehalose. Electroporation was performed at 150 V, 350 V, and 500 V. The miRNA-loaded exosomes were then co-incubated with cells. The efficiency of miRNA delivery was evaluated through fluorescence co-localization, nanoparticle tracking analysis, and qPCR. Our findings demonstrate that the Bio-Rad Gene Pulser Electroporation buffer is highly effective as an electroporation medium for exosomes. Optimal miRNA transfection efficiency and cellular uptake were achieved at 350 V, with significantly higher exosome internalization observed under these conditions. Utilizing the Bio-Rad Gene Pulser Electroporation buffer at 350 V enhances both miRNA loading efficiency into extracellular vesicles and subsequent cellular uptake. This study establishes an optimized electroporation protocol, addressing limitations in existing methodologies and advancing the potential of extracellular vesicles as a robust platform for miRNA-based therapeutic delivery.

Keywords:  Electroporation; Exosomes; MicroRNA; Platelet; Trehalose; Voltage

DOI:  https://doi.org/10.1007/s12033-026-01590-1
J Extracell Biol. 2026 Jul;5(7): e70159

Engineered Red Blood Cell-Derived Extracellular Vesicles With Klotho Peptide Protect the Kidney From Fibrosis.

Tunahan Ergunay, Alessia Brossa, Michela Arena, Stefania Bruno, Alessandro Gori, Anne Metje van Genderen, Rosalinde Masereeuw, Benedetta Bussolati.

  Chronic kidney disease is characterized by progressive tubular injury and fibrosis, ultimately leading to irreversible loss of renal function. Extracellular vesicles (EVs) have emerged as promising therapeutic platforms due to their biocompatibility and engineering potential. In this study, we engineered red blood cell-derived EVs to deliver an active peptide (RBC-EVKP1) from the anti-aging hormone klotho, as a targeted antifibrotic strategy. EVs were isolated from healthy donors and surface-functionalized with the peptide. Fibrosis was evaluated in proximal tubular epithelial cells exposed to TGFβ and in a 3D proximal tubule-on-chip model. RBC-EVKP1 treatment significantly attenuated TGFβ-induced fibrotic and mesenchymal gene expression, reduced extracellular matrix accumulation, and suppressed SMAD signaling. In addition, RBC-EVKP1 reduced cell migration and preserved epithelial organization. In the tubule-on-chip system, engineered EVs maintained cytoskeletal integrity and reduced injury-associated marker expression under fibrotic conditions. Collectively, these findings demonstrate that klotho-engineered EVs effectively inhibit TGFβ-driven fibrosis and preserve tubular integrity, highlighting a promising therapeutic strategy for targeting kidney fibrosis.

Keywords:  TGFβ; chronic kidney disease; exosome therapy; kidney fibrosis; organ‐on‐chip; therapeutic peptide

DOI:  https://doi.org/10.1002/jex2.70159
Nanomedicine (Lond). 2026 Jul 11. 1-19

Brain targeting and trafficking of extracellular vesicles in central nervous system diseases: a therapeutic roadmap.

Blaine Baker, Samuel Emerson, Taylor Tran, Nikita Mohapatra, David Wang, Thant Zaw, Aaleesha Doshi, Juan-Maria Lopez, Dua Hassan, Priyadarsini Kumar, Diana Farmer, Aijun Wang.

  Extracellular vesicles (EVs) mediate intercellular signaling in the central nervous system (CNS) by transferring lipids, proteins, and nucleic acids among neurons, glia, endothelium, and immune cells. Brain targeting depends on a linked sequence: EV ligands and adsorbed protein coronas engage receptor modules, select endocytic routes, determine intracellular fate, and define the therapeutic readouts. These fates include lysosomal degradation, recycling, rare cytosolic delivery, or transport across the blood-brain barrier (BBB). In disease, the same pathways can disseminate proteopathic seeds and amplify neuroinflammation. Heparan sulfate proteoglycans (HSPGs) and LDL receptor family members, including low-density lipoprotein receptor-related protein 1 (LRP1), regulate tau, α-synuclein, and amyloid-β handling. Phosphatidylserine readers and complement shape myeloid sink capture and inflammatory output. Integrin, tetraspanin, and ICAM-1 nanoclusters influence avidity, organotropism, and immune suppression. At the BBB, endothelial HSPGs, LRP1, and transferrin receptor (TfR) support receptor-mediated uptake, motivating engineered ligands such as rabies virus glycoprotein-derived peptides, Angiopep-2, and TfR binders. However, endosomal escape remains a major kinetic barrier to nucleic acid delivery. We synthesize these principles across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, glioblastoma, and demyelinating disease, and outline design and assay standards needed to translate EV biology into safe, manufacturable CNS therapeutics.

Keywords:  Extracellular vesicles; blood-brain barrier; endosomal escape; microglia; neurodegeneration; protein corona; receptor-mediated transcytosis; uptake logic

DOI:  https://doi.org/10.1080/17435889.2026.2698782