Serum stability enhancement of siRNA caused by peptide conjugation at 3'-terminus of sense strand

RNA interference has been widely used for gene therapy of various infectious diseases and malignant tumors. However, its poor stability in serum has limited further clinic application. Here, we found that stability of siRNA in serum enhanced obviously when 3′-terminus of sense strand （siRNA-pS） was conjugated with peptide, while same conjugation at 3′-terminus of antisense strand brought no such effects. And it was also found that only the peptide residue in siRNA-pS could be cut off by RNase A. All these results indicated that nucleases in serum prefer to invade siRNA duplex through the 3′-end of sense strand.

Serum-induced degradation of 3D DNA box origami observed with high-speed atomic force microscopy

3D DNA origami holds tremendous potential for the encapsulation and selective release of therapeutic drugs. Observations of the real-time performance of these structures in physiological environments will contribute to the development of future applications. We investigated the degradation kinetics of 3D DNA box origami in serum by using high-speed atomic force microscope optimized for imaging 3D DNA origami in real time. The time resolution allowed to characterize the stages of serum effects on individual 3D DNA boxes origami with nanometer resolution. Our results indicate that the digestion process is a combination of rapid collapse and slow degradation phases. Damage to box origami occurs mainly in the collapse phase. Thus, the structural stability of 3D DNA box origami should be improved, especially in the collapse phase, before these structures are used in clinical applications.

A glutathione-triggered precision explosive system for improving tumor chemosensitivity

Stimuli-responsive delivery systems hold promise in cancer treatments.However,their application potential has been limited due to undesirable drug leaking during blood circulation and inefficient therapeutic efficacy in tumors,resulting in undesirable therapeutic outcomes.Herein,we have developed a novel redox-sensitive pegylated phospholipid,termed as DOPE-SS-PEG,which can form a glutathione(GSH)-triggered precision explosive system(GPS)for simultaneously improving circulation stability,tumor specificity,and chemosensitivity,leading to explosive anticancer effects.GPS is constructed of liposomal doxorubicin(DOX)functionalized with DOPE-SS-PEG and MnO_(2) nanoparticles,which can protect liposome structure in the presence of serum GSH(20μM),whereas converts to cationic liposome in response to intracellular GSH(10 mM),thereby enhancing circulation stability,tumor specificity,endosomal escape,and cytoplasmic delivery.Importantly,GPS can not only generate oxygen to relieve hypoxia and consequently enhance chemosensitivity,but quench GSH antioxidability to elevate the accruement of intracellular reactive oxygen species(ROS),leading to an explosion of oxidative stress induced cell injury.Particularly,in vivo studies show that GPS selectively accumulates in tumor tissues,effectively inhibits tumor growth,exhibits minimal systemic adverse effects,and consequently prolongs the survival time of tumor-bearing mice.Therefore,GPS is a unique stimuli-responsive treatment with programmed and on-demand drug delivery,as well as explosive therapeutic efficacy,and provides an intelligent anticancer treatment.