Highly Effective Stroke Therapy Enabled by Genetically Engineered Viral Nanofibers.

Abstract

Stroke results in the formation of a cavity in the infarcted brain tissue. Angiogenesis and neurogenesis are poor in the cavity, preventing brain-tissue regeneration for stroke therapy. To regenerate brain tissue in the cavity, filamentous phages, the human-safe nanofiber-like bacteria-specific viruses, are genetically engineered to display many copies of RGD peptide on the sidewalls. The viral nanofibers, electrostatically coated on biocompatible injectable silk protein microparticles, not only promote adhesion, proliferation, and infiltration of neural stem cells (NSCs), but also induce NSCs to differentiate preferentially into neurons in basal medium within 3 d. After the NSC-loaded microparticles are injected into the stroke cavity of rat models, the phage nanofibers on the microparticles stimulate angiogenesis and neurogenesis in the stroke sites within two weeks for brain regeneration, leading to functional recovery of limb motor control of rats within 12 weeks. The viral nanofibers also brought about the desired outcomes for stroke therapy, such as reducing inflammatory response, decreasing thickness of astrocytes scars, and increasing neuroblasts response in the subventricular zone. As virtually any functional peptide can be displayed on the phage by genetic means, the phage nanofibers hold promise as a unique and effective injectable biomaterial for stroke therapy.