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Proteins are an important therapeutic modality in modern medicine. However, their inherent inability to traverse cell membranes essentially limits their application to extracellular targets. Recent advances in intracellular protein delivery have enabled access to traditionally "undruggable" intracellular targets and paved the way to precisely modulate cellular functions. This Review provides a comprehensive examination of the key mechanisms and emerging technologies that facilitate the transport of functional proteins across cellular membranes. Delivery methods are categorized into physical, chemical, and biological approaches, each with distinct advantages and limitations. Physical methods enable direct protein entry but often pose challenges related to invasiveness and technical complexity. Chemical strategies offer customizable solutions with enhanced control over cellular targeting and uptake, yet may face issues with cytotoxicity and scalability. Biological approaches leverage naturally occurring processes to achieve efficient intracellular transport, though regulatory and production consistency remain hurdles. By highlighting recent advancements, challenges, and opportunities within each approach, this review underscores the potential of intracellular protein delivery technologies to unlock new therapeutic pathways and transform drug development paradigms.
Xie et al. (Mon,) studied this question.