In situ poly I:C released from living cell drug nanocarriers for macrophage-mediated antitumor immunotherapy.

Immunotherapy is one of the most promising approaches to inhibit tumor growth and metastasis by activating host immune functions. However, the arising problems such as low immune response caused by complex tumor microenvironment and extremely systemic immune storm still limit the clinical applications of immunotherapy. Here, we construct Poly I: C-encapsulated poly (lactic-co-glycolic acid) nanoparticles (PLP NPs) with a slow release profile. A biomimetic system (MPLP), which loads PLP NPs on the surface of bone marrow-derived macrophage (BMDM) via the maleimide-thiol conjugation, is synthesized to effectively deliver PLP, control drug release and activate the tumor-specific immune response in situ. The results show that PLP NPs loading does not affect the activity and function of BMDM. Then, BMDM acts as a living cell drug vehicle and promotes the accumulation of PLP NPs in tumors, where Poly I: C is released from PLP NPs and reprograms BMDM into tumoricidal M1 macrophage. Furthermore, MPLP triggers potent antitumor immune responses in vivo and effectively inhibits local and metastatic tumors without causing adverse pathological immune reactions. This study offers an inspiration to facilitate clinical translation through the delivery of drugs by living immune cells for future anticancer therapy.

Dissecting complicated viral spreading of enterovirus 71 using in situ bioorthogonal fluorescent labeling.

Enterovirus 71 (EV71), the major pathogen of hand-foot-and-mouth disease (HFDM), can cause severe neurological and respiratory manifestations in young children. Viral spread route and tissue tropism are key factors contributing to different pathogenicity of EV71, however it remains a challenge to dynamically visualize EV71 infection in vivo. The present study applies an in situ bioorthogonal fluorescent labeling strategy to track clinically isolated EV71 strains with different pathogenicity in neonatal mice. The results show that the in situ labeling strategy effectively captures EV71 viruses through in vivo bioorthogonal reaction in multiple infected organs without interfering viral spread and tissue tropism. More importantly, the in situ labeling reveals different viral dynamics, dissemination, and tissue tropism of severe case EV71 (SC-EV71) and mild case EV71 (MC-EV71), consistent with their different pathogenicity in HFDM patients. Compared with MC-EV71, SC-EV71 not only enters the blood circulation and spreads out more quickly, but also shows more significant neuronal and respiratory tropism, which certainly contribute severe neurological complications and clinical manifestations in the patient. Hence, the in situ bioorthogonal fluorescent labeling is a plausible strategy to dissect complicated process of EV71 viral spread in the early stage of infection, thereby offering great opportunities to understand its pathogenesis and develop anti-viral drugs.