Surface charge of biological and medical nanocarriers has been demonstrated to play an important role in cellular uptake. Owing to the unique physicochemical properties, charge-reversal delivery strategy has rapidly developed as a promising approach for drug delivery application, especially for cancer treatment. Charge-reversal nanocarriers are neutral/negatively charged at physiological conditions while could be triggered to positively charged by specific stimuli (i.e., pH, redox, ROS, enzyme, light or temperature) to achieve the prolonged blood circulation and enhanced tumor cellular uptake, thus to potentiate the antitumor effects of delivered therapeutic agents. In this review, we comprehensively summarized the recent advances of charge-reversal nanocarriers, including: (i) the effect of surface charge on cellular uptake; (ii) charge-conversion mechanisms responding to several specific stimuli; (iii) relation between the chemical structure and charge reversal activity; and (iv) polymeric materials that are commonly applied in the charge-reversal delivery systems.Graphical Abstract

Chemodynamic therapy (CDT), a newly developed approach for cancer treatment, can convert hydrogen peroxide (H₂O₂) into toxic hydroxyl radicals (•OH) by using Fenton/Fenton-like reaction to kill tumor cells. However, due to the complexity of the intracellular environment of tumor cells, the therapeutic efficacy of CDT was severely restricted. Recently, combination therapy strategies have become popular approaches for tumor treatment, and there are numerous studies have demonstrated that the CDT-based combination strategies can significantly improve the anti-tumor efficiency of CDT. In this review, we outline some of the recent progress in cancer chemodynamic therapy from 2020, and discuss the progress in the design of nanosystems for CDT synergistic combination therapies.

Engineered circular RNAs (circRNAs) are a class of single-stranded RNAs with head-to-tail covalently linked structures that integrate open reading frames (ORFs) and internal ribosome entry sites (IRESs) with the function of coding and expressing proteins. Compared to mRNA vaccines, circRNA vaccines offer a more improved method that is safe, stable, and simple to manufacture. With the rapid revelation of the biological functions of circRNA and the success of Severe Acute Respiratory Coronavirus Type II (SARS-CoV-2) mRNA vaccines, biopharmaceutical companies and researchers around the globe are attempting to develop more stable circRNA vaccines for illness prevention and treatment. Nevertheless, research on circRNA vaccines is still in its infancy, and more work and assessment are needed for their synthesis, delivery, and use. In this review, based on the current understanding of the molecular biological properties and immunotherapeutic mechanisms of circRNA, we summarize the current preparation methods of circRNA vaccines, including design, synthesis, purification, and identification. We discuss their delivery strategies and summarize the challenges facing the clinical application of circRNAs to provide references for circRNA vaccine-related research.

A novel hyaluronic acid (HA)-modified hybrid nanocomplex HA-SeSe-COOH/siR-93C@PAMAM, which could efficiently deliver siRNA into tumor cells via a redox-mediated intracellular disassembly, was constructed for enhanced antitumor efficacy. Thereinto, siR-93C (siRNA) and positive PAMAM were firstly mixed into the electrostatic nano-intermediate, and then diselenide bond (-SeSe-)-modified HA was coved to shield excessive positive charges. This hybrid nanocomplex displayed uniform dynamic sizes, high stability, controlled zeta potential and narrow PDI distribution. Moreover, the -SeSe- linkage displayed GSH/ROS dual responsive properties, improving intracellular trafficking of siRNA. In vitro assays in A549 cell line presented that HA-SeSe-COOH/siR-93C@PAMAM has low cytotoxicity, rapid lysosomal escape and significant transfection efficiency; besides, an efficient proliferation inhibition ability and enhanced apoptosis. Furthermore, in animal studies, this negative-surfaced hybrid nanocomplex showed a prolonged circulation in blood and improved inhibition of tumor growth. All these results verified our hypothesis in this study that diselenide bonds-modified HA could promote not only stability and safety of nanoparticles in vivo but also intracellular behavior of siRNA via redox-dual sensitive properties; furthermore, this hybrid nanocomplex provided a visible potential approach for siRNA delivery in the antitumor field.