Abstract <p>Extracellular vesicles (EVs), are nanovesicles with a complex composition of lipids, proteins, and nucleic acids. These vesicles regulate cellular functions and play a crucial role in intercellular communication. Owing to their endogenous lipid-bilayer, EVs exhibit superior biocompatibility and internalize efficiently via pathways like membrane fusion or endocytosis. They traverse restrictive physiological hurdles such as the blood-brain barrier with a low immunogenic profile that minimizes the toxicities associated with synthetic carriers. These attributes position EVs as a transformative class of vehicles for precise molecular delivery and orchestrating complex tissue-repair processes in regenerative medicine. However, their clinical application remains challenging due to issues such as limited stability, low yield, and inefficient delivery to target tissues. The use of exogenous scaffolds, such as silk fibroin (SF) scaffolds, has emerged as a promising strategy for EVs delivery. SF, a natural fibrous protein, offers superior biocompatibility compared to commonly used biological polymers like collagen and poly L-lactic acid. Its biocompatibility, tunable mechanical properties, and capacity to support controlled release make it an ideal scaffold for encapsulating and protecting EVs. This review explores the unique properties of SF and its adaptability to diverse formats such as films, hydrogels, and nanoparticles. It summarizes the interactions between SF scaffolds and EVs, advanced fabrication strategies, and surface modification techniques designed to enhance EVs delivery and functionality. Furthermore, this comprehensive overview critically evaluates current fabrication strategies and applications, identifies key translational hurdles, and proposes future directions for designing advanced SF-EVs systems for superior therapeutic outcomes.</p> Lay Summary <p>EVs are tiny “message bubbles” produced by cells that contain powerful healing instructions. While they have huge potential for medicine, they are fragile and often washed away before they can work. This review highlights a potential solution: utilising silk from silkworms to construct protective “scaffolds.” These silk structures ranging from 3D-printed patches to injectable gels act as a delivery vehicle. They shield the EVs, keep them at the injury site, and release them slowly over time. By combining silk’s strength with the healing power of EVs, we can create smarter treatments for repairing bones, skin, and nerves more effectively.</p>