RVG29-modified oncolytic herpes simplex virus for intracranial tumor treatment

Oncolytic virus therapy for brain tumors has achieved breakthrough progress in clinical applications, yet its potential is severely constrained by the mode of administration-direct intratumoral injection into the cranial cavity. Other administration routes face rapid clearance by neutralizing antibodies and obstacles posed by the blood-brain barrier. Herein, we engineered the oncolytic herpes simplex virus type 2 (OH2) with surface modifications of polyethylene glycol (PEG) and rabies virus glycoprotein 29 (RVG29, a BBB-penetrating peptide from the rabies virus), to form OH2-PEG-RVG. OH2-PEG-RVG could efficiently traversed the blood-brain barrier even in BALB/c mice with pre-existing anti-OH2 antibodies, leading to the accumulation of OH2 in the brain. More importantly, OH2-PEG-RVG maintained blood-brain barrier integrity without causing pathological changes or behavioral abnormalities in mice. Furthermore, OH2-PEG-RVG effectively inhibited brain tumor growth, transforming immunologically "cold" tumors into "hot" tumors, inducing a robust anti-tumor immune response, and prolonging the survival of the mice. These findings underscore the potential of OH2-PEG-RVG as a multifaceted therapeutic strategy for effective brain tumor treatment, offering insights into addressing blood-brain barrier limitations.