Molecular Weight Engineering of Silk Proteins for Biomedical Applications: Strategies and Challenges

Silk proteins are natural biopolymers with outstanding mechanical properties and diverse biological functions. However, the extraction and processing of silk from cocoons inevitably alter their molecular weight (Mw) distributions, profoundly affecting physicochemical properties, bioactivity, and processability. In this review, we first outline the molecular structures and characteristics of silk fibroin (SF) and silk sericin (SS). We then systematically summarize current strategies for the regulation, characterization, and fractionation of silk protein Mw. Subsequently, we discuss the critical roles of Mw in the fabrication of silk-based materials, including particles, fibers, hydrogels, and micropatterned constructs, as well as its impact on key material properties such as mechanical performance and biodegradability. Furthermore, we highlight the Mw-dependent biological activities of silk proteins, including mitogenic, antioxidant, and immunomodulatory effects. Finally, we analyze challenges and perspectives, aiming to promote a Mw-oriented design paradigm that integrates the processing, structure, properties, and biological functions of silk protein materials.