Nanotechnology and nano-sized tools: Newer approaches to circumvent oncolytic adenovirus limitations

Oncolytic adenoviruses (OAds), engineered Ads preferentially infect and lyse tumor cells, have attracted remarkable attention as immunotherapy weapons for the treatment of various malignancies. Despite hopeful successes in preclinical investigations and translation into clinical phases, they face some challenges that thwart their therapeutic effectiveness, including low infectivity of cancer cells, liver sequestration, pre-existing neutralizing antibodies, physical barriers to the spread of Ads, and immunosuppressive TME. Nanotechnology and nano-sized tools provide several advantages to overcome these limitations of OAds. Nano-sized tools could improve the therapeutic efficacy of OAds by enhancing infectivity and cellular uptake, targeting and protecting from pre-existing immune responses, masking and preventing liver tropism, and co-delivery with other therapeutic agents. Herein, we reviewed the constructs of various OAds and their application in clinical trials, as well as the limitations they have faced. Furthermore, we emphasized the potential applications of nanotechnology to solve the constraints of OAds to improve their anti-tumor activities.