Liposomes are the most valuable nanocarriers in clinical use because of their biocompatibility, biodegradation, and effective encapsulation of hydrophilic or hydrophobic drugs. However, their applications are limited by the structure and functions of the most common phospholipids used as the main component of the liposomes. In this work, novel series of thioether phosphatidylcholines (S-PCs) and S-PC-based liposomes (S-LPs) were developed for reactive oxygen species (ROS)-responsive drug release. First of all, S-PCs with different chain lengths were synthesized by a combination of click reaction and heterogeneous esterification. Differential scanning calorimetry studies indicated that S-PCs had different phase transition temperatures depending on their chain lengths. Their critical aggregation concentrations were measured by the fluorescence probe technique indicating the self-assembly ability. After that, S-PC-based stealth liposomes (S-LPs) containing DSPE-PEG 2000 and cholesterol were prepared via a classic thin-film method. Doxorubicin (DOX) as a model drug was loaded in the stealth liposomes (DOX/S-LPs) by using the ammonium sulfate gradient method with high encapsulation efficiency. DOX/S-LPs were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), and cryogenic TEM, confirming their spherical structure with the bilayer thickness of about 4 nm. The ROS sensitivity of S-PCs and S-LPs was carefully evaluated in the presence of H 2 O 2 by means of mass spectrometry, DLS, TEM, and ultraviolet spectroscopy and release study. The results indicated the significant structural change of S-LPs after H 2 O 2 treatment, which demonstrated that S-LPs possessed an efficient ROS-triggered disintegration because of thioether oxidation of S-PCs. Finally, in vitro and in vivo anticancer efficiency assays revealed the improved drug potency of DOX/S-LPs, which can be attributed to ROS-triggered destruction of S-LPs after the uptake by tumor cells followed by rapid release of DOX. All together, as alternatives of traditional phosphatidylcholines, S-PC-based stealth liposomes are promising ROS-responsive carriers for the controlled delivery of drugs.

Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5′-monophosphate–mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid–sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5′-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum , namely tyrosine RS ( Pf YRS). ML901 exerts whole-life-cycle–killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.

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Artemisinin and its derivatives (artemisinins) are first‐line chemotherapeutic agents of lethal malaria, which also showed tremendous value in many other diseases including chronic inflammation. Unfortunately, almost all artemisinins are rapid‐acting medicines with an extremely short half‐life in vivo, which significantly limits their clinical application for these new adaptation diseases. In this study, a locally injectable long‐acting gene/artemisinin co‐delivery nano‐microplex consisting of a biodegradable hyaluronic acid (HA) microsphere and releasable gene/artemisinin co‐delivery nano‐lipoplex is developed first, to obtain an improved efficacy for rheumatoid arthritis (RA). Briefly, a cationic multicomponent drug‐embedded liposome with pharmacological activity is first reported based on two novel artemisinin derivatives (dAPC and dACC), which possess mimic phospholipids and cationic lipids, respectively. A cationic artemisinin‐embedded lipoplex is first reported as a medicative gene carrier here. An in situ injectable TNF‐α siRNA/artemisinin co‐delivery nano‐microplex (MTAsi@MG) is further prepared by immobilization of TNF‐α siRNA/lipoplex on porous microfluidic HA microspheres. Using this nano‐microplex for intra‐articular injection, the sustaining activity of gene therapy and artemisinin efficacy for RA long‐term treatment is first realized. Undoubtedly, this intra‐articular injectable TNF‐α siRNA/artemisinin co‐delivery nano‐microplex based on dAPC/dACC lipoplex and microfluidic microspheres would be one of the most potent gene/drug co‐delivery systems for RA therapy.