Immunotherapy approaches, including oncolytic virotherapy (OVT), offer cutting-edge and targeted strategies to fight cancer. Oncolytic viruses (OVs) refer to viruses that preferentially replicate in and lyse tumor cells, sparing normal cells from destructive effects (Ghajar-Rahimi et al., 2022). Although several viruses showed a natural tropism toward malignant cells, others require genetically engineering modifications to preferentially target cancer cells, including chemical or genetic modifications of viral surface for binding to upregulated receptors on a cancer cell, using tissue- or tumor-specific promoters, modifications of viral genes making them compatible to replicate in tumor cells, and regulation of gene expression in viruses using miRNAs (Naumenko et al., 2022). Tremendous studies in OVT led to the U.S. Food and Drug Administration (FDA) approval of Talimogene laherparepvec (T-Vec), an OV based on herpes simplex virus type I (HSV-1), as a therapeutic candidate for malignant melanoma in 2015 (Coffin, 2016). Besides T-Vec, Oncorine (H101) (China, for head and neck cancers, 2005), RIGVIR (Latvia, for melanoma, 2004), and Delytact (Teserpaturev) (Japan, for glioma, 2021) also translated from bench to bedside for the treatment of cancers (Dong et al., 2023). Among various types of viruses, adenoviruses (Ads) have several characteristics that make them ideally appropriate agents as next-generation oncolytic, including flexible backbone for genetic modifications, low pathogenicity, ability to infect both replicating and non-replicating cells, easy purification procedures, and high titer of virus production (Abudoureyimu et al., 2019; Mantwill et al., 2021).

In recent decades, nanotechnology and nano-sized tools have revolutionized different biomedicine areas, including the delivery of therapeutic agents, tracking them within the body, decontamination and monitoring of pollutants in the environment, and anti-bacterial properties (Goradel et al., 2023; Kang, Tahir, Wang, & Chang, 2021; Seyede Rahele Yousefi, Amiri, & Salavati-Niasari, 2019; Seyede Raheleh Yousefi, Alshamsi, Amiri, & Salavati-Niasari, 2021). Nanomaterials present excellent chemical and physical properties, such as protection of their cargo from fast clearance and degradation, the ability to target particular tissues, appropriate colloidal stability, good biocompatibility, high loading capacity, and low toxicity, making them suitable candidates to be used with other agents to improve their therapeutic efficacy in cancer treatment (Mattheolabakis & Mikelis, 2019; Morales-Cruz et al., 2019). Regarding cancer immunotherapy, it has been shown that nano-sized materials can effectively enhance host immune responses through ample and selective delivery of antigens and adjuvants to either immune sites or tumors (Baeza, 2020; Saeed et al., 2019). Nano-sized tools are being developed as promising platforms to augment the therapeutic effects of OVs and their safety in the treatment of various cancers. For instance, hyaluronic acid-coated thiolated chitosan nanoformulation enhanced sustained delivery and active targeted of oncolytic measles virus and inhibited tumor growth in breast cancer with acceptable safety (Naseer et al., 2023). Here, we will summarize oncolytic adenoviruses (OAds) application in clinical trials and the challenges they face in developing efficient and safe therapeutic agents. Our main focus will be on the most advancements in OAds and how nanotechnology and nano-sized tools help the field to overcome the challenges. These topics will give an overview for scientists and therapeutic developers against cancer to use convergence technologies, including genetic engineering, virology, and nanotechnology, for delivering safe, effective, and smart OAds to the TME.