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Surface-Engineered Exosomes for Targeted Drug and Gene Delivery to Cartilage /

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Surface-Engineered Exosomes for Targeted Drug and Gene Delivery to Cartilage // Tanvi Vinod Pathrikar.
Author:	Pathrikar, Tanvi Vinod,
Description:	1 electronic resource (141 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-06, Section: B.
基督教聖經之智慧書導讀 :	Osteoarthritis (OA) is a degenerative joint disease that affects multiple joint tissues and is a leading cause of pain and disability worldwide, yet it remains without a cure. Although several disease-modifying OA drugs (DMOADs) have been identified, they have largely failed in clinical trials. The dense, avascular, and negatively charged cartilage extracellular matrix (ECM), combined with the rapid clearance of therapeutic agents from the synovial joint space, presents significant challenges for the efficient transport and sustained delivery of drugs to chondrocytes embedded deep within the tissue. Exosomes, nanoscale extracellular vesicles secreted by cells, have emerged as promising vehicles for drug delivery due to their non-immunogenic properties and role in intercellular communication. However, exosomes have a negative surface charge due to their lipid bilayer which is repelled by the anionic cartilage matrix. This doctoral thesis addresses these challenges by developing surface-engineered, cartilage-targeting exosomes as non-viral carriers for gene therapy and drug delivery in OA. In the first aim, exosomes are surface-engineered by anchoring optimally charged, cartilage-targeting arginine-rich motifs onto the anionic exosome bilayer, utilizing buffer pH as a charge-reversal mechanism. When intra-articularly injected into destabilized medial meniscus mice knees with early-stage OA, these engineered exosomes demonstrated the ability to penetrate the full thickness of the cartilage.Receptor antagonist of Interleukin-1 (IL-1RA) prevents the activation of catabolic pathways triggered by Interleukin-1 in OA. In the second aim, the surface-engineered exosomes are modified by loading them with IL-1RA to target highly negatively charged cartilage tissue, forming intra-cartilage depots for sustained IL-1RA delivery. By anchoring cartilage-targeting cationic motifs onto bovine milk-derived exosomes and loading IL-1RA on both the surface and within the exosomes, the formulations effectively penetrated and were retained in the full thickness of early-stage arthritic cartilage. These formulations significantly suppressed cytokine-induced catabolism with a single dose. Finally, gene therapy holds promise for cartilage repair in osteoarthritis (OA) by programming the cells to express the disease-modifying molecules endogenously. Viral vector-mediated gene delivery has shown potential to a greater extent but is limited by concerns over immunogenicity and cytotoxicity. To address these challenges, aim three explores the applicability of surface-engineered exosomes as non-viral carriers for gene therapy in OA. These engineered exosomes efficiently delivered encapsulated eGFP and IL-1RA mRNA to chondrocytes in deep tissue layers. In destabilized medial meniscus mouse models with early-stage OA, intra-articular injection of eGFP mRNA-loaded engineered exosomes overcame joint clearance, penetrated cartilage, created an intra-tissue depot, and expressed eGFP effectively, whereas native exosomes did not. This suggests strong translational potential for these engineered exosomes as a platform technology for cartilage-targeted non-viral delivery of therapeutic mRNA for OA treatment.In conclusion, these findings demonstrate the potential of surface-engineered exosomes as a cell-free platform for sustained OA drug delivery. The engineered exosome formulations effectively delivered IL-1RA and IL-1RA mRNA, successfully targeting early-stage arthritic cartilage and offering a promising approach to improving localized therapeutic efficacy in OA treatment.
Contained By:	Dissertations Abstracts International86-06B.
Subject:	Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31761090
ISBN:	9798346866862

Surface-Engineered Exosomes for Targeted Drug and Gene Delivery to Cartilage /
Pathrikar, Tanvi Vinod,

Surface-Engineered Exosomes for Targeted Drug and Gene Delivery to Cartilage /Tanvi Vinod Pathrikar. - 1 electronic resource (141 pages)

Source: Dissertations Abstracts International, Volume: 86-06, Section: B.

Osteoarthritis (OA) is a degenerative joint disease that affects multiple joint tissues and is a leading cause of pain and disability worldwide, yet it remains without a cure. Although several disease-modifying OA drugs (DMOADs) have been identified, they have largely failed in clinical trials. The dense, avascular, and negatively charged cartilage extracellular matrix (ECM), combined with the rapid clearance of therapeutic agents from the synovial joint space, presents significant challenges for the efficient transport and sustained delivery of drugs to chondrocytes embedded deep within the tissue. Exosomes, nanoscale extracellular vesicles secreted by cells, have emerged as promising vehicles for drug delivery due to their non-immunogenic properties and role in intercellular communication. However, exosomes have a negative surface charge due to their lipid bilayer which is repelled by the anionic cartilage matrix. This doctoral thesis addresses these challenges by developing surface-engineered, cartilage-targeting exosomes as non-viral carriers for gene therapy and drug delivery in OA. In the first aim, exosomes are surface-engineered by anchoring optimally charged, cartilage-targeting arginine-rich motifs onto the anionic exosome bilayer, utilizing buffer pH as a charge-reversal mechanism. When intra-articularly injected into destabilized medial meniscus mice knees with early-stage OA, these engineered exosomes demonstrated the ability to penetrate the full thickness of the cartilage.Receptor antagonist of Interleukin-1 (IL-1RA) prevents the activation of catabolic pathways triggered by Interleukin-1 in OA. In the second aim, the surface-engineered exosomes are modified by loading them with IL-1RA to target highly negatively charged cartilage tissue, forming intra-cartilage depots for sustained IL-1RA delivery. By anchoring cartilage-targeting cationic motifs onto bovine milk-derived exosomes and loading IL-1RA on both the surface and within the exosomes, the formulations effectively penetrated and were retained in the full thickness of early-stage arthritic cartilage. These formulations significantly suppressed cytokine-induced catabolism with a single dose. Finally, gene therapy holds promise for cartilage repair in osteoarthritis (OA) by programming the cells to express the disease-modifying molecules endogenously. Viral vector-mediated gene delivery has shown potential to a greater extent but is limited by concerns over immunogenicity and cytotoxicity. To address these challenges, aim three explores the applicability of surface-engineered exosomes as non-viral carriers for gene therapy in OA. These engineered exosomes efficiently delivered encapsulated eGFP and IL-1RA mRNA to chondrocytes in deep tissue layers. In destabilized medial meniscus mouse models with early-stage OA, intra-articular injection of eGFP mRNA-loaded engineered exosomes overcame joint clearance, penetrated cartilage, created an intra-tissue depot, and expressed eGFP effectively, whereas native exosomes did not. This suggests strong translational potential for these engineered exosomes as a platform technology for cartilage-targeted non-viral delivery of therapeutic mRNA for OA treatment.In conclusion, these findings demonstrate the potential of surface-engineered exosomes as a cell-free platform for sustained OA drug delivery. The engineered exosome formulations effectively delivered IL-1RA and IL-1RA mRNA, successfully targeting early-stage arthritic cartilage and offering a promising approach to improving localized therapeutic efficacy in OA treatment.

English

ISBN: 9798346866862Subjects--Topical Terms:

187040
Immunology.
Subjects--Index Terms:

Gene delivery

Surface-Engineered Exosomes for Targeted Drug and Gene Delivery to Cartilage /
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520 $a Osteoarthritis (OA) is a degenerative joint disease that affects multiple joint tissues and is a leading cause of pain and disability worldwide, yet it remains without a cure. Although several disease-modifying OA drugs (DMOADs) have been identified, they have largely failed in clinical trials. The dense, avascular, and negatively charged cartilage extracellular matrix (ECM), combined with the rapid clearance of therapeutic agents from the synovial joint space, presents significant challenges for the efficient transport and sustained delivery of drugs to chondrocytes embedded deep within the tissue. Exosomes, nanoscale extracellular vesicles secreted by cells, have emerged as promising vehicles for drug delivery due to their non-immunogenic properties and role in intercellular communication. However, exosomes have a negative surface charge due to their lipid bilayer which is repelled by the anionic cartilage matrix. This doctoral thesis addresses these challenges by developing surface-engineered, cartilage-targeting exosomes as non-viral carriers for gene therapy and drug delivery in OA. In the first aim, exosomes are surface-engineered by anchoring optimally charged, cartilage-targeting arginine-rich motifs onto the anionic exosome bilayer, utilizing buffer pH as a charge-reversal mechanism. When intra-articularly injected into destabilized medial meniscus mice knees with early-stage OA, these engineered exosomes demonstrated the ability to penetrate the full thickness of the cartilage.Receptor antagonist of Interleukin-1 (IL-1RA) prevents the activation of catabolic pathways triggered by Interleukin-1 in OA. In the second aim, the surface-engineered exosomes are modified by loading them with IL-1RA to target highly negatively charged cartilage tissue, forming intra-cartilage depots for sustained IL-1RA delivery. By anchoring cartilage-targeting cationic motifs onto bovine milk-derived exosomes and loading IL-1RA on both the surface and within the exosomes, the formulations effectively penetrated and were retained in the full thickness of early-stage arthritic cartilage. These formulations significantly suppressed cytokine-induced catabolism with a single dose. Finally, gene therapy holds promise for cartilage repair in osteoarthritis (OA) by programming the cells to express the disease-modifying molecules endogenously. Viral vector-mediated gene delivery has shown potential to a greater extent but is limited by concerns over immunogenicity and cytotoxicity. To address these challenges, aim three explores the applicability of surface-engineered exosomes as non-viral carriers for gene therapy in OA. These engineered exosomes efficiently delivered encapsulated eGFP and IL-1RA mRNA to chondrocytes in deep tissue layers. In destabilized medial meniscus mouse models with early-stage OA, intra-articular injection of eGFP mRNA-loaded engineered exosomes overcame joint clearance, penetrated cartilage, created an intra-tissue depot, and expressed eGFP effectively, whereas native exosomes did not. This suggests strong translational potential for these engineered exosomes as a platform technology for cartilage-targeted non-viral delivery of therapeutic mRNA for OA treatment.In conclusion, these findings demonstrate the potential of surface-engineered exosomes as a cell-free platform for sustained OA drug delivery. The engineered exosome formulations effectively delivered IL-1RA and IL-1RA mRNA, successfully targeting early-stage arthritic cartilage and offering a promising approach to improving localized therapeutic efficacy in OA treatment.
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