Cancer is one of the world's largest health problems.Based on global demographic characteristics, the incidence of cancer is predicted to increase by 2025 with more than 20 million new cancer cases per year (Zugazagoitia et al., 2016). Until the early 20th century, oncotherapy was performed in the form of surgical removal of tumor tissue. It was the time of Virchow, Lister, Koch, Pasteur, and the dramatic advances in science and technology (Kelly and Russell, 2007a). Then, there was a huge evolution in medical oncology and new treatments such as radiation therapy and chemotherapy were introduced. Here, we first review in detail the various mechanisms of oncotherapy through oncolytic viruses and nanoparticle-based therapies. Then, to overcome the challenges and reduce the limitations, we directed the study towards nano-based oncolytic viruses combination therapy, which represents significant and promising advances in combination therapy of cancer in the near future.

Historically, immunooncotherapy dates back to the late 1800 s. An American investigators used coli toxin derived from the bacterial exotoxins of Streptococcus pyogenes and Serratia marseccans to treat solid tumors (Raja et al., 2018). Traditional immunotherapy still has many shortcomings, such that immunogenic cell death, destruction of healthy tissue, and high toxicity were severe side effects of these treatment methods (Bouzid et al., 2020). Patients who have received immunotherapy have shown only up to 30 % objective effectiveness (Iwai et al., 2017). Generally, new therapeutic methods should be proposed that have precise tumor targeting and less toxic side effects. As a result, researchers directed oncotherapy to gene and viral therapy. The first gene therapy was performed in 1990 (Misra, 2013), which opened a new therapeutic path, and with great effort, several gene therapy products were approved. It should be noted that to date the most common disease treated with gene therapy is cancer, which accounts for more than 60 % of clinical trials. After that, monogenetic and cardiovascular diseases include about 11 % and 7 % of cases, respectively (Ginn et al., 2018a). Viruses are known to cause 20 % of human cancers. In this regard, it can mention Burkitt's lymphoma, liver carcinoma, and Kaposi's sarcoma, are caused by Epstein-Barr virus, hepatitis B, and C, respectively (Iwai et al., 2017). In addition to the role of viruses in the development of tumors, Duran I Reynals had already welcomed the virus for the treatment of diseases (Alemany, 2013). Then, the antitumor effects of viruses were gradually discovered in the late 19th century. In 1904, the first documented association between a natural viral infection and a potential anticancer effect was discovered by Dr. George Duck. This report involved a woman with leukemia who experienced a decrease in leukocyte counts following a natural influenza virus infection (Arabi et al., 2022). Many studies were conducted to discover the oncolytic ability of different types of viruses. Researchers started with wild viruses, but the results were unsatisfactory due to the uncontrollability of wild viruses. With the advent of genetic engineering through knockouts and/or knockins of specific genes in the viral genome, virulence can be attenuated, and tumor specificity of the virus can be improved, making the use of viruses in cancer therapy a reality (Lauer and Beil, 2022). In this study, we focus on the functional mechanism of OVs in the context of oncotherapy and discuss innovative strategies used to optimize the potential of OVs.

Gene therapy is a technique that transfers genetic material to cells to reverse an abnormal condition or induce a new characteristic, and it has shown great potential for the treatment of various diseases. For this purpose, various strategies are used such as: adding, editing, deleting, and deactivating the target area. The first time, the idea of using gene therapy for genetic disorders was applied (Ginn et al., 2018a). The viral and non-viral vectors have been used to transfer genetic material. Although non-viral vectors are promising for practical use in terms of relative safety and low cost, their effectiveness has not yet been proven (Hidai and Kitano, 2018). Several studies have reported the gene transfer efficiency of viral vectors to be 10–1000 times that of non-viral vectors (Varga et al., 2005, Hama et al., 2006). The most common gene transfer vectors used in clinical trials are adenoviral (Ad) vectors, retroviral vectors, and naked plasmids (Ginn et al., 2018b). However, there are several major drawbacks to viral vectors, including immunogenicity, cytotoxicity, the limited capacity of the virus to transfer genes, and a phenomenon called insertional mutagenesis. This means that, by aberrant integration of the virus genome, the disrupted tumor suppressor gene or oncogene is activated, which leads to the malignant transformation of cells. There have also been reports of deaths following the administration of viral vectors for gene transfer (Mohammadinejad et al., 2020, David and Doherty, 2017). Adeno-associated virus (AAV)-based vectors have shown impressive results. In-vivo delivery of AAV vectors to the nervous system, retina, and liver led to the recovery of patients with spinal muscular atrophy, congenital blindness, and hemophilia B, respectively (Dunbar et al., 2018).

In 2003, the China Food and Drug Administration (SFDA) approved Gendicine for head and neck cancer (Zhang et al., 2018). In 2012, Glybera was approved by the European Medicines Agency (EMA) for lipoprotein lipase deficiency (Gruber, 2012) Strimvelis, the first ex-vivo gene therapy product, was approved by the EMA in 2016 for the treatment of ADA-SCID (Seimetz et al., 2019). The first in-vivo AAV gene therapy product called Luxturna for Leber's congenital amaurosis (LCA) was also approved by the US Food and Drug Administration FDA in 2017 (Padhy et al., 2020). An AAV vector, Zolgensma, received FDA approval in 2019 for pediatric spinal muscular atrophy (Mahajan, 2019). The number of approved products shows an upward trend every year. Although most of the clinical trials are related to cancer (especially hematological cancers) (Junghans, 2017), due to the evolution of gene therapy strategies over time and successful clinical results, gene therapy has created a new perspective for the treatment of a wide range of diseases.