Piperazine-derived ionizable lipids for enhanced mRNA delivery and cancer immunotherapy

Messenger ribonucleic acid(mRNA)-based therapeutics hold great prospects in disease treatment and lipid nanoparticles(LNPs)are the most extensively applied non-viral platform for RNA delivery in clinics.Despite the clinical success of LNPs as vehicles have been achieved,developing LNPs with enhanced mRNA transmembrane delivery and transfection efficiency in a non-toxic manner is highly desirable and challenging.In this study,we designed a series of new ionizable amino lipids with piperazinederived headgroups and constructed a group of LNPs to promote the transfection activity of mRNA cargos.Among them,LNP formulated with lipid 10(L10-LNP)can efficiently package mRNA and perform superior transfection efficiency both in vitro and in vivo,which is mainly attributed to the improved intracellular uptake and effective endosomal escape.We verified that a single administration of L10-LNP packaging interleukin(IL)-12 mRNA induced tumor shrink and even regression by robust activation of immune effector CD8^(+)T cells and stimulating the generation of IFN-γwithout causing systemic toxicity,which provides a promising platform for clinical cancer immunotherapy.

The lasso structure,biosynthesis,bioactivities and potential applications of Microcin J25:A novel antibacterial agent with unique mechanisms

The overuse and misuse of traditional antimicrobial drugs have led to their weakened effectiveness and the emergence of pathogenic bacterial resistance.Consequently,there has been growing interest in alternative op-tions such as antimicrobial peptides(AMPs)in the pharmaceutical industry.Microcin J25(MccJ25)has gained significant attention for its potent inhibitory effect on a diverse range of pathogens.Its unique rotaxane structure provides exceptional stability against extreme thermal,pH,and protease degradation,including chymotrypsin,trypsin,and pepsin.Given its remarkable stability and diverse bioactivity,we aim to provide an overview of the physicochemical properties,the mechanism underlying its antimicrobial activity,and the critical functional residues of MccJ25.Additionally,we have summarized the latest strategies for the heterologous expression of MccJ25,and its potential medical use and other applications.

Progress in transdermal drug delivery systems for cancer therapy

Transdermal drug delivery is an appealing option except for oral and hypodermic administration.With the advancement of skin penetration strategies,various anticancer therapeutics ranging from liphilic small-molecule drugs to hydrophilic biomacromolecules,can be administered transdermally,offering an optional regimen to treat skin cancers.In addition,the activation of the skin immune systems can also assist the treatment of distal sites.Current approaches on enhancing the transdermal delivery efficacy of anticancer drugs are summarized in this review.We also survey recent advances in micro-and nanotechnology-based transdermal formulations for cancer treatment,such as chemotherapy,gene therapy,immunotherapy,phototherapy and combination therapy.New penetration enhancers,materials,formulations and their hypothesized mechanisms for transdermal delivery are highlighted.Advantages and limitations regarding the state-of-the-art transdermal delivery technologies,as well as future perspective are also discussed.

Emerging electrochemical sensors for life healthcare

As electrochemical sensors possess unique potential properties that are strongly related to their high sensitiv-ity,selectivity and cycling stability,making it extensively used in versatile fields of biosensing,electrochemical analysis and drug delivery.Notably,recent evidence demonstrates that electrochemical technology provides a promising platform for life healthcare by biocompatibility of mimicking human tissue to report electrical signals,potentially enabling timely disorder prediction through non-invasive real time and simultaneous health monitoring.This review focuses on the comprehensive set of advances in the field of electrochemical devices for life healthcare,including fabrication,analytical performance,and their multiple applications in clinical settings are deliberated.

Enzyme-instructed hybrid nanogel/nanofiber oligopeptide hydrogel for localized protein delivery

Enzyme-catalysis self-assembled oligopeptide hydrogel holds great interest in drug delivery,which has merits of biocompatibility,biodegradability and mild gelation conditions.However,its application for protein delivery is greatly limited by inevitable degradation of enzyme on the encapsulated proteins leading to loss of protein activity.Moreover,for the intracellularly acted proteins,cell membrane as a primary barrier hinders the transmembrane delivery of proteins.The internalized proteins also suffer from acidic and enzymatic degradation in endosomes and lysosomes.We herein develop a proteasemanipulated hybrid nanogel/nanofiber hydrogel for localized delivery of intracellularly acted proteins.The embedded polymeric nanogels(CytoC/aNGs)preserve activity of cytochrome c(CytoC)that is an intracellular activator for cell apoptosis as a model protein against proteolysis,and do not affect the gelation properties of the protease-catalysis assembled hydrogels.The injectable hydrogel(CytoC/aNGs/Gel)serves as a reservoir to enhance intratumoral retention and realize sustainable release of CytoC/aNGs.The released CytoC/aNGs increase cellular uptake of CytoC and enhance its intracellular delivery to its target site,cytoplasm,resulting in favorable apoptosis-inducing and cytotoxic effects.We show that a single local administration of CytoC/aNGs/Gel efficiently inhibit the tumor growth in the breast tumor mouse model.

Emerging prospects of protein/peptide-based nanoassemblies for drug delivery and vaccine development

Proteins have been widely used in the biomedical field because of their well-defined architecture,accurate molecular weight,excellent biocompatibility and biodegradability,and easy-to-functionalization.Inspired by the wisdom of nature,increasing proteins/peptides that possess self-assembling capabilities have been explored and designed to generate nanoassemblies with unique structure and function,including spatially organized conformation,passive and active targeting,stimuli-responsiveness,and high stability.These characteristics make protein/peptide-based nanoassembly an ideal platform for drug delivery and vaccine development.In this review,we focus on recent advances in subsistent protein/peptide-based nanoassemblies,including protein nanocages,virus-like particles,self-assemblable natural proteins,and self-assemblable artificial peptides.The origin and characteristics of various protein/peptide-based assemblies and their applications in drug delivery and vaccine development are summarized.In the end,the prospects and challenges are discussed for the further development of protein/peptide-based nanoassemblies.