Oncolytic virotherapy (OVT) is a promising approach in cancer immunotherapy. Oncolytic viruses (OVs) could be applied in cancer immunotherapy without in-depth knowledge of tumor antigens. The capability of genetic modification makes OVs exciting therapeutic tools with a high potential for manipulation. Improving efficacy, employing immunostimulatory elements, changing the immunosuppressive tumor microenvironment (TME) to inflammatory TME, optimizing their delivery system, and increasing the safety are the main areas of OVs manipulations. Recently, the reciprocal interaction of OVs and TME has become a hot topic for investigators to enhance the efficacy of OVT with less off-target adverse events. Current investigations suggest that the main application of OVT is to provoke the antitumor immune response in the TME, which synergize the effects of other immunotherapies such as immune-checkpoint blockers and adoptive cell therapy. In this review, we focused on the effects of OVs on the TME and antitumor immune responses. Furthermore, OVT challenges, including its moderate efficiency, safety concerns, and delivery strategies, along with recent achievements to overcome challenges, are thoroughly discussed.

Natural extracellular vesicles (EVs) are nanoscale vesicles derived from diverse biological sources, recognized for their roles in intercellular communication and therapeutic cargo delivery. Due to their intrinsic biocompatibility, low immunogenicity, and ability to traverse biological barriers, EVs have garnered increasing interest as oral drug delivery vehicles. However, despite growing preclinical research, there is currently no comprehensive review that systematically focuses on EVs specifically for oral delivery applications-a critical gap in the literature. This review aims to systematically summarize and critically assess the current progress in the development of EVs as oral drug delivery systems. It integrates knowledge on EVs sources, extraction and engineering strategies, and their therapeutic potential across a range of diseases. By addressing this underexplored yet promising area, the review seeks to establish a foundational reference for both basic researchers and clinical innovators. The review provides a comparative analysis of EVs from animal and plant origins, emphasizing their stability in the gastrointestinal tract and their ability to encapsulate and protect bioactive molecules. It explores the mechanisms by which EVs overcome physiological barriers such as intestinal epithelium and the blood-brain barrier (BBB), and how surface modifications enhance tissue targeting. The review covers therapeutic applications in oncology, neurodegenerative, metabolic, inflammatory, and infectious diseases, highlighting advantages in improving oral bioavailability and reducing side effects. It also identifies current challenges in standardization, large-scale production, and drug loading efficiency. The review concludes by proposing future directions for optimizing EVs-based oral delivery systems and facilitating their clinical translation.