Boarding pyroptosis onto nanotechnology for cancer therapy.

Pyroptosis, a non-apoptotic programmed cellular inflammatory death mechanism characterized by gasdermin (GSDM) family proteins, has gathered significant attention in the cancer treatment. However, the alarming clinical trial data indicates that pyroptosis-mediated cancer therapeutic efficiency is still unsatisfactory. It is essential to integrate the burgeoning biomedical findings and innovations with potent technology to hasten the development of pyroptosis-based antitumor drugs. Considering the rapid development of pyroptosis-driven cancer nanotherapeutics, here we aim to summarize the recent advances in this field at the intersection of pyroptosis and nanotechnology. First, the foundation of pyroptosis-based nanomedicines (NMs) is outlined to illustrate the reliability and effectiveness for the treatment of tumor. Next, the emerging nanotherapeutics designed to induce pyroptosis are overviewed. Moreover, the cross-talk between pyroptosis and other cell death modalities are discussed, aiming to explore the mechanistic level relationships to provide guidance strategies for the combination of different types of antitumor drugs. Last but not least, the opportunities and challenges of employing pyroptosis-based NMs in potential clinical cancer therapy are highlighted.

Engineered bacterial outer membrane vesicles encapsulating oncolytic adenoviruses enhance the efficacy of cancer virotherapy by augmenting tumor cell autophagy.

Oncolytic adenovirus (Ad) infection promotes intracellular autophagy in tumors. This could kill cancer cells and contribute to Ads-mediated anticancer immunity. However, the low intratumoral content of intravenously delivered Ads could be insufficient to efficiently activate tumor over-autophagy. Herein, we report bacterial outer membrane vesicles (OMVs)-encapsulating Ads as microbial nanocomposites that are engineered for autophagy-cascade-augmented immunotherapy. Biomineral shells cover the surface antigens of OMVs to slow their clearance during in vivo circulation, enhancing intratumoral accumulation. After entering tumor cells, there is excessive H2O2 accumulation through the catalytic effect of overexpressed pyranose oxidase (P2O) from microbial nanocomposite. This increases oxidative stress levels and triggers tumor autophagy. The autophagy-induced autophagosomes further promote Ads replication in infected tumor cells, leading to Ads-overactivated autophagy. Moreover, OMVs are powerful immunostimulants for remolding the immunosuppressive tumor microenvironment, facilitating antitumor immune response in preclinical cancer models in female mice. Therefore, the present autophagy-cascade-boosted immunotherapeutic method can expand OVs-based immunotherapy.

Emerging systemic delivery strategies of oncolytic viruses: A key step toward cancer immunotherapy.

Oncolytic virotherapy (OVT) is a novel type of immunotherapy that induces anti-tumor responses through selective self-replication within cancer cells and oncolytic virus (OV)-mediated immunostimulation. Notably, talimogene laherparepvec (T-Vec) developed by the Amgen company in 2015, is the first FDA-approved OV product to be administered via intratumoral injection and has been the most successful OVT treatment. However, the systemic administration of OVs still faces huge challenges, including in vivo pre-existing neutralizing antibodies and poor targeting delivery efficacy. Recently, state-of-the-art progress has been made in the development of systemic delivery of OVs, which demonstrates a promising step toward broadening the scope of cancer immunotherapy and improving the clinical efficacy of OV delivery. Herein, this review describes the general characteristics of OVs, focusing on the action mechanisms of OVs as well as the advantages and disadvantages of OVT. The emerging multiple systemic administration approaches of OVs are summarized in the past five years. In addition, the combination treatments between OVT and traditional therapies (chemotherapy, thermotherapy, immunotherapy, and radiotherapy, etc.) are highlighted. Last but not least, the future prospects and challenges of OVT are also discussed, with the aim of facilitating medical researchers to extensively apply the OVT in the cancer therapy.