Journal
JOURNAL OF EXTRACELLULAR VESICLES
Volume 10, Issue 4, Pages -Publisher
WILEY
DOI: 10.1002/jev2.12057
Keywords
conjugation; delivery; extracellular vesicles; targeted; therapeutics
Categories
Funding
- National University of Singapore [NUHSRO/2019/076/STARTUP/02]
- Hong Kong Innovation and Technology Commission [ITS/201/18]
- Hong Kong Health and Medical Research Fund [05160296, 06172196]
- National Natural Science Foundation of China [81770099, 81773246, 81972865]
- Shenzhen Innovation and Technology Fund [JCYJ20180507181636165, JCYJ20170413115637100, JCYJ20170412152916724]
- Hong Kong Research Grants Council [21101218]
- Hong Kong Children's Thalassemia Foundation [2018/01]
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centre of Excellence initiative
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The study presents a novel method for covalently conjugating EVs with targeting moieties using protein ligases, enabling specific delivery of therapeutic payloads to target cells without the need for genetic and chemical modifications. This approach shows promise for enhancing drug efficacy in cancer therapy by targeting specific receptors on cancer cells.
Natural extracellular vesicles (EVs) are ideal drug carriers due to their remarkable biocompatibility. Their delivery specificity can be achieved by the conjugation of targeting ligands. However, existing methods to engineer target-specific EVs are tedious or inefficient, having to compromise between harsh chemical treatments and transient interactions. Here, we describe a novel method for the covalent conjugation of EVs with high copy numbers of targeting moieties using protein ligases. Conjugation of EVs with either an epidermal growth factor receptor (EGFR)-targeting peptide or anti-EGFR nanobody facilitates their accumulation in EGFR-positive cancer cells, both in vitro and in vivo. Systemic delivery of paclitaxel by EGFR-targeting EVs at a low dose significantly increases drug efficacy in a xenografted mouse model of EGFR-positive lung cancer. The method is also applicable to the conjugation of EVs with peptides and nanobodies targeting other receptors, such as HER2 and SIRP alpha, and the conjugated EVs can deliver RNA in addition to small molecules, supporting the versatile application of EVs in cancer therapies. This simple, yet efficient and versatile method for the stable surface modification of EVs bypasses the need for genetic and chemical modifications, thus facilitating safe and specific delivery of therapeutic payloads to target cells.
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