Overcoming resistance in oncolytic virotherapy: Nano-engineered solutions for systemic delivery and efficacy boost

Oncolytic virotherapy (OVT) has emerged as a transformative cancer treatment, leveraging tumor-selective viral replication to induce direct oncolysis and stimulate systemic antitumor immunity. Despite clinical advancements, including the FDA-approved T-VEC and subsequent agents, significant challenges remain, particularly in systemic delivery and therapeutic efficacy optimization. Intratumoral administration is largely restricted to superficial lesions, whereas intravenous delivery is hindered by rapid immune clearance due to viral antigen exposure. Additionally, insufficient antitumor efficacy presents another major hurdle, driving the growing trend of combinatorial therapies that exert synergistic effects. To overcome these barriers, nanotechnology-driven strategies, encompassing masking, targeting, and arming approaches, are revolutionizing OVT by enhancing viral stealth, improving tumor specificity, and amplifying therapeutic efficacy. Furthermore, considering biosafety concerns associated with live viral therapeutics, alternative functional nanoparticles that mimic oncolytic virus activity have been developed. These include synthetic oncolytic viruses, oncolytic peptides and polymers empowered by nanotechnology, and structurally mimetic nanoparticles. These engineered nanosystems have demonstrated potent oncolytic activity, positioning them as promising alternatives to traditional OVs while retaining their tumor-lytic functions. In this review, we explore how nanotechnology is redefining oncolytic virotherapy, focusing on masking, targeting, and arming nano-strategies. Additionally, we comprehensively examine the potential of nanoparticles to mimic and even replace oncolytic viruses, offering new avenues for enhanced cancer treatment.