*3.5. Administration Routs*

One of the factors influencing the response to OVT is the way of administration. Intratumoral injection results in precise control of the OV concentration in the TME, resulting in better therapeutic outcomes [255,256]. However, the complexity of intratumoral injection limits dosing repetition [257]. Besides, low perfusion of OVs into dense tumors requires ECM-degradation strategies [226]. Intravenous injection is popular due to its convenience, reproducibility, and possibility to target metastatic foci [258,259]. However, it requires

tumor- specific delivery systems and is more likely to cause systemic toxicity [257]. Liver tropism, physical barriers such as BBB, complement activation, and the immune system response to OV before accessing the TME are the other disadvantages of intravenous injection [226,257]. Intraperitoneal, intrathecal/intracranial, and intrapleural injections are suitable for targeting intra-abdominal organs, central nervous system (CNS), and lung tumors, respectively, but are limited to use in laboratory animals [153]. The best route of administration is still a matter of debate with no specific guidelines. It seems that the less aggressive administration routs such as oral/mucosal and nasal administration, at least for gastrointestinal and cerebral malignancies, could increase the acceptability for patients and should be considered in future studies.
