Anchor, Spacer, and Ligand-Modified Engineered Exosomes for Trackable Targeted Therapy

Abstract

Exosomes have been widely demonstrated as an effective anticancer therapeutic moiety. However, their clinical translation has been limited by the requirement of prohibitively high therapeutic doses due to their lack of specificity in delivery and, consequently, short systemic half-life. To overcome these challenges, we engineered a platform for modifying exosomes with an active targeting modality composed of membrane Anchor (BODIPY)-Spacer (PEG)-targeting Ligands (cyclic RGD peptide) (ASL). Herein, we show that the intramembrane incorporation of a trackable, targeting system renders ASL exosomes (AExs) a modular platform. AExs significantly overcome challenges associated with exosome modification, including potential damage for functionalization, or destabilizing interactions between dyes and drugs. ASL-modification not only enhanced stability in imparting active targeting but also introduced a built-in bioimaging modality. Our studies show that AExs target B16F10 melanoma tumor sites by the specific interaction of cyclic RGD and integrin. Doxorubicin encapsulated AExs (dAExs) significantly inhibited the growth of melanoma in vitro and in vivo. Thus, we conclude that ASL-modification allows exosomes to be transformed into a novel therapeutic vehicle uniquely integrating in vivo tracking and robust targeting with drug delivery. We anticipate that the therapeutic, targeting, and diagnostic modularity provided by ASL will potentiate translational applications of exosome-based vehicles beyond anticancer therapy.

Bioinspired soft nanovesicles for site‐selective cancer imaging and targeted therapies

“…Especially, exosomes have been widely documented as a versatile platform for anticancer therapeutic applications, but, their clinical translation is slow and limited with the lack of specific delivery, high therapeutic doses requirement, and short half‐life (<10 min; Jiang et al, 2021; Kang et al, 2020). Therefore, to overcome these encounters and develop exosomes as a promising delivery platform, exosomes have been modified with active targeting agents, namely, membrane anchor (BODIPY)‐spacer (PEG)‐targeting ligands (cyclic RGD peptide; ASL; Kang et al, 2020). Chemical conjugation and genetic transfection have been considered as promising approaches for surface modification of exosomes based systems.…”

“…Moreover, ASL modification improves the circulation, targeting ability, and stability of exosomes in cancer mimicked environment where doxorubicin‐loaded ASL‐modified exosomes significantly reduce the growth of melanoma at in vitro and in vivo levels. Hence, surface‐modified exosomes could be considered as a novel therapeutic system (Jiang et al, 2021; Kang et al, 2020).…”

“…Various nanosized platforms suffer from poor targeting ability, low biocompatibility, low blood circulation, poor stability, nonspecific distribution, and so forth (Ye et al, 2019). To improve these abilities, surface modifiers such as Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), folic acid, PEGylation, antibodies, peptides, and so forth have been decorated on the surface of nanosized platforms, namely, exosomes, membrane nanovesicles, plasma membranes, liposomes, and so forth (Jiang et al, 2021;Kang et al, 2020;Prasad et al, 2018Prasad et al, , 2020. Especially, exosomes have been widely documented as a versatile platform for anticancer therapeutic applications, but, their clinical translation is slow and limited with the lack of specific delivery, high therapeutic doses requirement, and short half-life (<10 min; Jiang et al, 2021;Kang et al, 2020).…”

“…To improve these abilities, surface modifiers such as Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), folic acid, PEGylation, antibodies, peptides, and so forth have been decorated on the surface of nanosized platforms, namely, exosomes, membrane nanovesicles, plasma membranes, liposomes, and so forth (Jiang et al, 2021;Kang et al, 2020;Prasad et al, 2018Prasad et al, , 2020. Especially, exosomes have been widely documented as a versatile platform for anticancer therapeutic applications, but, their clinical translation is slow and limited with the lack of specific delivery, high therapeutic doses requirement, and short half-life (<10 min; Jiang et al, 2021;Kang et al, 2020). Therefore, to overcome these encounters and develop exosomes as a promising delivery platform, exosomes have been modified with active targeting agents, namely, membrane anchor (BODIPY)spacer (PEG)-targeting ligands (cyclic RGD peptide; ASL; Kang et al, 2020).…”

Exosome Traceability and Cell Source Dependence on Composition and Cell-Cell Cross Talk

“…Arg-Gly-Asp (RGD) peptide was used as a specific targeting ligand for integrin, which is overexpressed in melanoma. This system exhibits active targeting of B16F10 cells, more cellular uptake, and specific target accumulation leading to tumor growth inhibition in vitro and in vivo [86]. Other research used CP05 peptide specified as phage display for targeting, capturing, and cargo loading for exosomes by binding to the CD63, a well-known exosomal protein marker [87].…”