Oncolytic virotherapy (OVT) has emerged as a transformative approach in cancer treatment due to its unique capacity for tumor-selective replication and dual mechanism of action. Central to its therapeutic value, oncolytic viruses (OVs) exploit the impaired antiviral defenses of cancer cells to achieve preferential replication and direct oncolysis, while simultaneously stimulating systemic antitumor immunity through the release of tumor-associated antigens and activation of both innate and adaptive immune responses (DePeaux and Delgoffe, 2024, Zhong et al., 2025). The 2015 U.S. Food and Drug Administration (FDA) approval of talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1 (oHSV-1), marked a pivotal milestone, with subsequent approvals including Delytact, Oncorine, and Virgo further validating the clinical potential of OVs (Andtbacka et al., 2015). Recent advances have continued to expand the OV arsenal, exemplified by recombinant Newcastle disease virus (NDV-GT) engineered with the porcine α1,3GT gene (Zhong et al., 2025). In a registered clinical trial (ChiCTR2000031980), NDV-GT achieved a 90 % disease control rate in refractory metastatic cancers, underscoring its translational relevance.

Despite these successes, overcoming resistance remains a central challenge in OVT development. Barriers such as rapid immune clearance, pre-existing antiviral immunity, insufficient intratumoral delivery, and suboptimal immunogenicity significantly limit therapeutic efficacy. Notably, all FDA-approved OVs rely on intratumoral administration (Musher et al., 2024a), restricting treatment to accessible or superficial lesions and highlighting the unmet need for effective systemic delivery. Systemic administration offers improved feasibility and potential antimetastatic benefits (Jirovec et al., 2024), yet circulating OVs are rapidly recognized by Toll-like receptors (TLRs), neutralizing antibodies, and complement components, resulting in swift immunologic clearance. Masking strategies—by introducing external nanostructures onto the virion surface—have therefore emerged as promising approaches to shield OVs from antiviral responses, prolong circulation, and enhance tumor-targeted delivery through the enhanced permeability and retention (EPR) effect (Ban et al., 2023, Chen et al., 2024, Zhao et al., 2024). Alongside protection, precise navigation systems are equally essential to maximize therapeutic specificity (Huang et al., 2022, Zhao et al., 2024). Indeed, insufficient tumor tropism and antiviral resistance heavily contribute to the limited efficacy of current OVs, prompting increasing interest in complementary arming strategies and combination therapies (Dummer et al., 2025, Ressler et al., 2025).

In this context, nanotechnology, nanomedicine, and nanoscale biomaterials provide powerful tools to address multiple resistance barriers simultaneously (Chen et al., 2024, Huang et al., 2019, Li et al., 2024, Liang et al., 2023, Wang et al., 2024). Nanoplatforms can enable tailored delivery of OVs (Xu et al., 2025), while polymers, lipids, inorganic materials, and hybrid nanosystems offer robust viral masking to prevent neutralization and prolong circulation. Their intrinsic tumor-targeting capabilities, mediated by the EPR effect (Cooley et al., 2024) and further enhanced through ligand-based active targeting, significantly improve OV accumulation at tumor sites. Nanocarriers also support tumor microenvironment–responsive release, increasing delivery specificity and overcoming stromal and immune-mediated resistance. Importantly, nanomedicine facilitates the construction of multifunctional therapeutic systems (Pan et al., 2025, You et al., 2025): co-loading OVs with immunomodulators, adjuvants, or chemotherapeutics enhances antitumor potency and mitigates antiviral barriers; certain nanomaterials even possess inherent immune-modulating or cytotoxic properties that augment OV efficacy. In summary, nano-reprogramming of OVs—encompassing advanced masking, precise targeting, and integrated arming strategies—offers a promising pathway to overcome key resistance mechanisms in OVT, enhancing systemic delivery, immune evasion, intratumoral accumulation, and therapeutic potency (Table 1 and Fig. 1).