In Situ Sustained Delivery of Tumor Cell-Derived Extracellular Nanovesicles With Oncolytic Adenoviruses for Potentiating Cancer Immunotherapy.

Oncolytic adenoviruses (OVs) can directly eliminate cancer cells and subsequently activate immune responses, exhibiting potent antitumor therapeutics. However, it was observed that the immune cells can also be lysed during viral treatment, evidently dampening the OVs-mediated antitumor immune response. In this study, we develop a microneedle (MN)-based in situ tumor cell-derived extracellular nanovesicle (TDEV)-cloaked OVs platform to enhance cancer immunotherapy and reduce immune cell exhaustion. In this platform, tumor cells pre-infected with OVs are loaded into the upper reservoir of the MN device. Following the transdermal administration, the hollow MN would constantly facilitate the transport of in situ the generated TDEV-encapsulating OVs into the tumor site for sustained delivery of OVs, which could subsequently infect cancer cells selectively rather than immune cells. Enhanced antigens triggered by improved intratumoral OVs killing can be presented by non-exhausted dendritic cells, further evoking significant immunotherapeutic effects in both TC-1-hCD46 xenograft tumor-bearing mice and postoperative tumor recurrence mice models.