Exosomes hold great potential in therapeutic development. However, native exosomes usually induce insufficient effects in vivo and simply act as drug delivery vehicles. Herein, we synthesize responsive exosome nano‐bioconjugates for cancer therapy. Azide‐modified exosomes derived from M1 macrophages are conjugated with dibenzocyclooctyne‐modified antibodies of CD47 and SIRPα (aCD47 and aSIRPα) through pH‐sensitive linkers. After systemic administration, the nano‐bioconjugates can actively target tumors through the specific recognition between aCD47 and CD47 on the tumor cell surface. In the acidic tumor microenvironment, the benzoic‐imine bonds of the nano‐bioconjugates are cleaved to release aSIRPα and aCD47 that can, respectively, block SIRPα on macrophages and CD47, leading to abolished “don't eat me” signaling and improved phagocytosis of macrophages. Meanwhile, the native M1 exosomes effectively reprogram the macrophages from pro‐tumoral M2 to anti‐tumoral M1.

Although adoptive T-cell therapy has been successful in hematological malignancy treatment, its application in solid tumors remains a great challenge. Here, using a pH-sensitive benzoic−imine bond and inverse electrondemand Diels−Alder cycloaddition, we prepared magnetic nanoclusters (NCs) armed with responsive PD-1 antibody (aP), which could then bind onto effector T cells due to their PD-1 expression. After adoptive transfer, the magnetization and superparamagnetism of NCs enabled us to magnetically recruit effector T cells and aP simultaneously to tumor sites with MRI guidance. Owing to the acidic intratumoral microenvironment, the benzoic−imine bond then hydrolyzed, leading to the release of aP. The therapeutic effects of adoptive T cells and free aP could thus be spatiotemporally coupled. As a result, we achieved inhibition of tumor growth with few side effects, demonstrating the great promise of such a chemical approach for safe and high-performance adoptive T-cell therapy against solid tumors.

Lauric acid is a bioactive root exudate component in crown daisy. Mi-flp-18 is a pivotal gene regualting nematode chemotaxis and infection. Lauric acid regulates the nematode chemotaxis and disrupts the Mi-flp-18 expression in a concentration-dependent manner

Real-time tracking of the dynamic process of virus invasion is crucial to understanding the infection mechanism. For successful tracking, efficient labeling methods are indispensable. In this paper, we report a mild and reliable method for labeling viruses, especially with regard to easily disabled enveloped viruses. The copper-free click chemistry has been used to label enveloped viruses with quantum dots (QDs) by linking virions modified with azide to the QDs derived with dibenzocyclooctynes (DBCO). Both vaccinia virus (VACV) and avian influenza A virus (H9N2) can be specifically and rapidly labeled under mild conditions, with a labeling efficiency of more than 80%. The labeled virions were of intact infectivity, and their fluorescence was strong enough to realize single-virion tracking. Compared to previously reported methods, our method is less destructive, reliable, and universal, without specific requirements for the type and structure of viruses to be labeled, which has laid the foundation for long-term dynamic visualization of virus infection process.

Extracellular vesicles (EVs) hold great potential in both disease treatment and drug delivery. However, accurate drug release from EVs, as well as the spontaneous treatment effect cooperation of EVs and drugs at target tissues, is still challenging. Here, an engineered self‐activatable photo‐EV for synergistic trimodal anticancer therapy is reported. M1 macrophage‐derived EVs (M1 EVs) are simultaneously loaded with bis[2,4,5‐trichloro‐6‐(pentyloxycarbonyl) phenyl] oxalate (CPPO), chlorin e6 (Ce6), and prodrug aldoxorubicin (Dox‐EMCH). After administration, the as‐prepared system actively targets tumor cells because of the tumor‐homing capability of M1 EVs, wherein M1 EVs repolarize M2 to M1 macrophages, which not only display immunotherapy effects but also produce H2O2. The reaction between H2O2 and CPPO generates chemical energy that activates Ce6, creating both chemiluminescence for imaging and singlet oxygen (1O2) for photodynamic therapy (PDT). Meanwhile, 1O2‐induced membrane rupture leads to the release of Dox‐EMCH, which is then activated and penetrates the deep hypoxic areas of tumors. The synergism of immunotherapy, PDT, and chemotherapy results in potent anticancer efficacy, showing great promise to fight cancers.

No abstract

Extracellular vesicles (EVs) have shown great potential in drug delivery, disease diagnosis, and treatment owing to their versatile native features and functions. RNA interference (RNAi) therapeutics that block the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway have attracted increasing interest for the treatment of various cancers. Here, immunoregulatory EVs are developed by decorating M1-macrophagederived EVs (M1 EV) with vesicular stomatitis virus glycoprotein (VSV-G), a pH-responsive viral fusion protein, and electroporating anti-PD-L1 siRNA (siPD-L1) into the EVs. After administration to CT26 tumor-bearing mice, this virus-mimic nucleic acid engineered EVs (siRNA@V-M1 EV) can target tumor tissues, which is attributed to the natural tumor-homing property of M1 EV. Then, the fusion of VSV-G with cells facilitates the direct release of siPD-L1 into the cytoplasm and triggers robust gene silencing, leading to the efficient block of PD-L1/PD-1 interaction and then the elevation of CD8 + T cell population. Meanwhile, the M1 EVs and IFN-γ secreted by the CD8 + T cells promote the repolarization of M2 tumor-associated macrophages to M1 macrophages. The combination of PD-L1/PD-1 pathway blocking, T cell recognition reconstructing, and M1 macrophage repolarization via multifunctional EVs can achieve satisfactory antitumor efficacy in this tumor model, showing potential as a new modality to fight cancers.

Oncolytic adenovirus (OA) is an ideal candidate for clinical anticancer treatment, because it can specifically replicate in tumor cells with high titer. However, its systemic administration is still hindered, because of severely compromised antitumor efficacy. Herein, an engineered OA was innovatively developed by enwrapping OA with calcium and manganese carbonates (MnCaCs) biomineral shell, which could protect the virus from removal of the host immune system and prolong its in vivo circulation. Upon accumulating in tumor sites, MnCaCs readily dissolved under the acidic microenvironment, releasing Mn 2+ that could convert endogenous H 2 O 2 into oxygen (O 2 ) and then enhance the duplication ability of OA, thus significantly increased the antitumor efficacy. Meanwhile, Mn 2+ and the increased O 2 individually endowed the T1 modal magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) feasibility, providing real-time monitoring information for the therapy. This versatile engineered OA demonstrated its promise for visible and efficient oncolytic virotherapy by systemic administration.