Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy

Reddy, Shivakumar K; Ballal, Abhijna R; Shailaja, S; Seetharam, Raviraja N; Raghu, Chandrashekar H; Sankhe, Runali; Pai, Kanthilatha; Tender, Tenzin; Mathew, Mary; Aroor, Annayya; Shetty, Ashok K; Adiga, Shalini; Devi, Vasudha; Muttigi, Manjunatha S; Upadhya, Dinesh

doi:10.7150/thno.78426

Cited by 28 publications

(12 citation statements)

References 65 publications

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“…Various methods have been explored for loading therapeutic cargo to sEVs, including techniques such as sonication, electroporation, freeze-thawing, and co-incubation. Notably, passive loading of sEVs through co-incubation has demonstrated efficacy in delivering anti-VEGF antibodies, effectively reducing neoangiogenesis in vivo in a rat retinopathy model [ 29 ]. In this study, passive loading via simple co-incubation at room temperature was employed, chosen for its simplicity and minimal impact on sEV membrane integrity compared to various alternative methods.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of umbilical cord extracellular vesicles and rhBMP-2 to enhance the regeneration of a metaphyseal femoral defect in osteoporotic rats

Deluca,

Wagner,

Heimel

et al. 2024

Stem Cell Res Ther

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Background The aim of this study was to evaluate potential synergistic effects of a single, local application of human umbilical cord MSC-derived sEVs in combination with a low dose of recombinant human rhBMP-2 to promote the regeneration of a metaphyseal femoral defect in an osteoporotic rat model. Methods 6 weeks after induction of osteoporosis by bilateral ventral ovariectomy and administration of a special diet, a total of 64 rats underwent a distal femoral metaphyseal osteotomy using a manual Gigli wire saw. Defects were stabilized with an adapted Y-shaped mini-locking plate and were subsequently treated with alginate only, or alginate loaded with hUC-MSC-sEVs (2 × 109), rhBMP-2 (1.5 µg), or a combination of sEVs and rhBMP-2 (n = 16 for each group). 6 weeks post-surgery, femora were evaluated by µCT, descriptive histology, and biomechanical testing. Results Native radiographs and µCT analysis confirmed superior bony union with callus formation after treatment with hUC-MSC-sEVs in combination with a low dose of rhBMP-2. This finding was further substantiated by histology, showing robust defect consolidation 6 weeks after treatment. Torsion testing of the explanted femora revealed increased stiffness after application of both, rhBMP-2 alone, or in combination with sEVs, whereas torque was only significantly increased after treatment with rhBMP-2 together with sEVs. Conclusion The present study demonstrates that the co-application of hUC-MSC-sEVs can improve the efficacy of rhBMP-2 to promote the regeneration of osteoporotic bone defects.

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Section: Discussionmentioning

confidence: 99%

Synergistic effect of umbilical cord extracellular vesicles and rhBMP-2 to enhance the regeneration of a metaphyseal femoral defect in osteoporotic rats

Deluca,

Wagner,

Heimel

et al. 2024

Stem Cell Res Ther

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“…A study by Gu et al 114 revealed that intravitreal administration of ADSC-EVs delivered miR‐192, which negatively regulates ITGA1, thus delaying the events of inflammation and angiogenesis. In another study of Reddy et al 115 , BMSC-EVs loaded with bevacizumab, an anti-VEGF antibody commonly used to treat DR, reduced retinal leakages, leukocytosis, and cell apoptosis in a rat model of DR. Moreover, the combination of EVs and bevacizumab prolongs the therapeutic effect from one month to two months, indicating the diverse application possibilities of MSC-EVs for DR treatment.…”

Section: Ev-based Therapy In Drmentioning

confidence: 94%

“…Utilizing EVs as a drug delivery platform is advantageous due to their specifical membrane-bound structure. The combination of drugs and EVs exerts a prolonged and better treatment benefit than either drug or native EVs administration alone 115 . However, when compared to conventional drugs, very few studies have reported the cellular uptake and vitreous pharmacokinetics of EVs after injection into retina.…”

Section: Ev-based Therapy In Drmentioning

confidence: 99%

Emerging role of extracellular vesicles in diabetic retinopathy

Zhu,

Huang,

Sun

et al. 2024

Theranostics

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Diabetic retinopathy (DR), a complex complication of diabetes mellitus (DM), is a leading cause of adult blindness. Hyperglycemia triggers DR, resulting in microvascular damage, glial apoptosis, and neuronal degeneration. Inflammation and oxidative stress play crucial roles during this process. Current clinical treatments for DR primarily target the advanced retinal disorder but offer limited benefits with inevitable side effects. Extracellular vesicles (EVs) exhibit unique morphological features, contents, and biological properties and can be found in cell culture supernatants, various body fluids, and tissues. In DR, EVs with specific cargo composition would induce the reaction of receptor cell once internalized, mediating cellular communication and disease progression. Increasing evidence indicates that monitoring changes in EV quantity and content in DR can aid in disease diagnosis and prognosis. Furthermore, extensive research is investigating the potential of these nanoparticles as effective therapeutic agents in preclinical models of DR. This review explores the current understanding of the pathological effects of EVs in DR development, discusses their potential as biomarkers and therapeutic strategies, and paves the way for further research and therapeutic advancements.

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“…In general, it was observed that almost 30% of the drug was loaded into the EVs. The produced BZ loaded EVs (BZ-EVs) retained the characteristic anti-angiogenic properties of BZ and demonstrated the ability to suppress VEGF levels in diabetic retinopathy [ 107 ]. Additionally, the extrusion method is also utilized to introduce drugs into EVs by repetitively passing them through a polycarbonate membrane with uniform-sized pores.…”

Section: Engineering Methods Of Ev and Applications For Regenerative ...mentioning

confidence: 99%

Recent advances in extracellular vesicle engineering and its applications to regenerative medicine

Rhim,

Kim,

Lee

et al. 2023

Biomater Res

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Extracellular vesicles (EVs) are nanosized particles that are released from cells and reflect the characteristics of the mother cell. Recently, the EVs have been used in several types of studies across many different fields. In the field of EV research, multiple cell culture and EV isolation techniques have been highlighted in importance. Various strategies, including exclusive component culture media, three-dimensional (3D) cultures, and hypoxic conditions, have been proposed for the cell culture to control function of the EVs. Ultracentrifugation, ultrafiltration, precipitation, and tangential flow filtration (TFF) have been utilized for EV isolation. Although isolated EVs have their own functionalities, several researchers are trying to functionalize EVs by applying various engineering approaches. Gene editing, exogenous, endogenous, and hybridization methods are the four well-known types of EV functionalization strategies. EV engineered through these processes has been applied in the field of regenerative medicine, including kidney diseases, osteoarthritis, rheumatoid arthritis, nervous system-related diseases, and others. In this review, it was focused on engineering approaches for EV functionalization and their applications in regenerative medicine.Graphical Abstract

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Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy

Cited by 28 publications

References 65 publications

Synergistic effect of umbilical cord extracellular vesicles and rhBMP-2 to enhance the regeneration of a metaphyseal femoral defect in osteoporotic rats

Synergistic effect of umbilical cord extracellular vesicles and rhBMP-2 to enhance the regeneration of a metaphyseal femoral defect in osteoporotic rats

Emerging role of extracellular vesicles in diabetic retinopathy

Recent advances in extracellular vesicle engineering and its applications to regenerative medicine

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