Niosomes from 80s to present: The state of the art

Efficient and safe drug delivery has always been a challenge in medicine. The use of nanotechnology, such as the development of nanocarriers for drug delivery, has received great attention owing to the potential that nanocarriers can theoretically act as “magic bullets” and selectively target affected organs and cells while sparing normal tissues. During the last decades the formulation of surfactant vesicles, as a tool to improve drug delivery, brought an ever increasing interest among the scientists working in the area of drug delivery systems. Niosomes are self assembled vesicular nanocarriers obtained by hydration of synthetic surfactants and appropriate amounts of cholesterol or other amphiphilic molecules. Just like liposomes, niosomes can be unilamellar or multilamellar, are suitable as carriers of both hydrophilic and lipophilic drugs and are able to deliver drugs to the target site. Furthermore, niosomal vesicles, that are usually non-toxic, require less production costs and are stable over a longer period of time in different conditions, so overcoming some drawbacks of liposomes.     

Controlling the Stealth Effect of Nanocarriers through Understanding the Protein Corona

The past decade has seen a significant increase in interest in the use of polymeric nanocarriers in medical applications. In particular, when used as drug vectors in targeted delivery, nanocarriers could overcome many obstacles for drug therapy. Nevertheless, their application is still impeded by the complex composition of the blood proteins covering the particle surface, termed the protein corona. The protein corona complicates any prediction of cell interactions, biodistribution, and toxicity. In particular, the unspecific uptake of nanocarriers is a major obstacle in clinical studies. This Minireview provides an overview of what we currently know about the characteristics of the protein corona of nanocarriers, with a focus on surface functionalization that reduces unspecific uptake (the stealth effect). The ongoing improvement of nanocarriers to allow them to meet all the requirements necessary for successful application, including targeted delivery and stealth, are further discussed.     

Zwitterionic polymers: Addressing the barriers for drug delivery

Nanocarriers play an important role in drug delivery for disease treatment. However, nanocarriers face a series of physiological barriers after administration such as blood clearance, nonspecific tissue/cell localization, poor cellular uptake, and endosome trapping. These physiological barriers seriously reduce the accumulation of drugs in target action site, which results in poor therapeutic efficiency. Although polyethylene glycol (PEG) can increase the blood circulation time of nanocarriers, its application is limited due to the “PEG dilemma”. Zwitterionic polymers have been emerging as an appealing alternative to PEG owing to their excellent performance in resisting nonspecific protein adsorption. Importantly, the diverse structures bring functional versatility to zwitterionic polymers beyond nonfouling. This review focuses on the structures and characters of zwitterionic polymers, and will discuss and summarize the application of zwitterionic polymers for drug delivery. We will highlight the strategies of zwitterionic polymers to address the physiological barriers during drug delivery. Finally, we will give some suggestions that can be utilized for the development of zwitterionic polymers for drug delivery. This review will also provide an outlook for this field. Our aim is to provide a comprehensive and systemic review on the application of zwitterionic polymers for drug delivery and promote the development of zwitterionic polymers.     

Understanding on the Surfactants Engineered Morphology Evolution of Block Copolymer Particles and Their Precise Mesoporous Silica Replicas

Surfactant-directed block copolymer(BCP) particles have gained intensive attention owing to their attractive morphologies and ordered domains. However, their controllable fabrication suffers several limitations including complex design and synthesis of multiple surfactant systems, limited choices of block copolymers, and time-consuming post-processes, etc. Herein, a surfactant size-dependent phase separation route is proposed to precisely manipulate the architectures of the anionic block copolymer particles in the binary co-assembly system of BCP and surfactants. In the system of polystyrene block polyacrylic acid (PS-b-PAA) and quaternary ammonium surfactants, it is verified that facile control on the ordered phase separation structures and morphologies of BCP particles can be achieved via simply varying the alkyl lengths of the surfactants. The cationic surfactants are demonstrated participating in the fabrication of the internal structures of BCP particles. Especially, it is found that the cationic surfactants are integrate into the anionic polyacrylic acid(PAA) domain of BCP particles of PS-b-PAA to influence the volume fraction of PAA blocks, so that varied architectures of BCP particles are constructed. Based on these understandings, spherical or ellipsoidal BCP particles are obtained as expected, as well as their precisely inorganic mesoporous silica replicas through the block copolymer nanoparticle replicating route. More interestingly, the ellipsoidal mesoporous silica exhibits higher cellular internalization capability due to its lower energy expenditure during the internalization process, which presents promising potentials in biomedical applications, especially for high-efficient drug delivery systems. These findings may provide valuable insights into the confinement assembly of anionic block copolymers and the creation of special nanocarriers for high-efficiency biomacromolecule delivery in the biomedical community.     

活性氧刺激响应纳米载体

纳米载体一般是由天然高分子或人工合成高分子组成的、纳米级范畴的运输系统,具有减少药物毒性、提高药物的靶向性、增加药物有效性等优点。随着生物医学技术的进步,有研究表明,作为氧化代谢产物的活性氧(ROS)在疾病部位常常伴随着过表达的异常现象。基于此,近年来ROS刺激响应纳米载体获得了关注和发展,以不同响应机制的ROS响应基团为基础,发展了一系列的ROS响应纳米载体,实现了疾病部位ROS刺激下的药物特异性可控释放。该文聚焦于近年来常用于纳米载体的ROS响应基团,依据元素划分为两大类:硫族元素类响应基团(硫醚、缩硫酮、硒化物、二硒化物、碲化物)和其他元素类响应基团(芳香硼酸酯、过氧草酸酯、二茂铁);通过不同的设计理念将其引入纳米载体,根据ROS响应纳米载体的不同响应机制(疏水-亲水相变、断裂),探讨了载体各自的ROS响应情况、体外药物释放情况,以及在活体中的应用情况。     

Dendrimers and miktoarm polymers based multivalent nanocarriers for efficient and targeted drug delivery

The delivery of biologically active agents to the desired site in the body and intracellular organelles is still a big challenge despite efforts made for more than five decades. With the elaboration of synthetic methodologies to branched and hyperbranched macromolecules such as miktoarm stars and dendrimers, the focus has shifted to nanocarriers able to release and direct drug molecules to a desired location in a controlled manner. We present here recent developments in the field of targeted drug delivery with a focus on two specific macromolecular nanocarriers, dendrimers and miktoarm stars, and provide examples of these nanocarriers tested in different biological systems. A particular attraction of miktoarm stars is their versatility in achieving superior drug loading within their self-assembled structures. Advantages of dendrimers over linear polymers are that the former provide a platform for development of multivalent and multifunctional nanoconjugates, in addition to their ability to accommodate a large number of molecules inside, or at their surfaces.     

DNA origami nanostructures for controlled therapeutic drug delivery

DNA nanostructures are emerging as a versatile platform for controlled drug delivery as a result of recent progress in production yield and strategies to obtain prolonged stability in biological environments. The construction of nanostructures from this unique biomaterial provides unparalleled control over structural and functional parameters. Recent applications of DNA origami-based nanocarriers for therapeutic drug delivery in preclinical phases highlight them as promising alternatives to conventional nanomaterials, as they benefit from the inherent favorable properties of DNA including biocompatibility and precise spatial addressability. By incorporating targeting aptamers and responsive properties into the nanocarrier design, more selective DNA origami-based nanocarriers are successfully prepared. On the other hand, current systems remain poorly understood in terms of biodistribution, final fate, and controlled drug release. As such, advances are needed to translate this material platform in its full potential for therapeutic applications.     

Calcium Phosphate Nanocarriers Dual‐Loaded with Bovine Serum Albumin and Ibuprofen: Facile Synthesis,Sequential Drug Loading and Sustained Drug Release

A simple and green strategy is reported for the preparation, drug loading, and release properties of a drug delivery system consisting of calcium phosphate (CP) nanocarriers dual‐loaded with bovine serum albumin (BSA) and hydrophobic drug ibuprofen (IBU). The sequential loading of BSA and IBU in calcium phosphate nanocarriers and in vitro simultaneous release of BSA and IBU are realized and investigated. In this method, BSA, which is used as a model protein drug, is encapsulated in situ in calcium phosphate nanocarriers. Subsequently, the typical hydrophobic drug IBU is loaded in the BSA/CP drug delivery system, forming the IBU/BSA/CP dual drug delivery system. The experiments reveal that the preloaded BSA not only reduces the cytotoxicity of calcium phosphate nanocarriers but also significantly improves the IBU drug loading capacity in calcium phosphate nanocarriers and greatly extends the duration of drug release. Thus, the as‐prepared IBU/BSA/CP dual drug delivery system is promising for drug delivery applications.     

Recent development in near infrared light-responsive polymeric materials for smart drug-delivery systems

Stimuli-responsive drug delivery systems (DDS) may overcome the drawbacks of conventional chemotherapy for cancer treatment. In particular, light-responsive polymer-based DDS may ensure spatio and temporal control in drug delivery. In this regard, near infrared (NIR) light triggered drug nanocarriers present several advantages when compared to UV–visible light triggered nanocarriers. This review surveys the recent development on the design, synthesis, functions, and applications of NIR photo-sensitive compounds in the development of long-wavelength light-responsive nanocarriers. Diverse NIR light responsive groups such as coumarin (CM), ortho-nitrobenzyl (ONB), 2-diazo-1,2-naphthoquinone (DNQ) and spiropyran (SP) derivatives and their photo-cleavage reaction mechanisms are discussed, as well as the use of indocyanine green (ICG) and its photo-thermal application. The loading into polymeric nanocarriers of up converting nanoparticles (UCNPs) which can convert NIR light into UV or visible light is also discussed. The described DDS are classified on the basis on the photo responsive groups. In details, the behavior of different polymeric materials such as micelles, hydrogels bearing photo responsive groups linked to bioactive molecules which are released under NIR light irradiation is reviewed and discussed. A section relative to commonly used instrument setup for drug release studies by NIR light irradiation is also presented for better understanding how the light has been used to irradiate in various experimental situations.     

Efficient exosome extraction through the conjugation of superparamagnetic iron oxide nanoparticles for the targeted delivery in rat brain

Exosomes possess endogenous attributes and distinct biological functions, and thereby, their uses as drug nanocarriers have attracted increasing attention for biomedical practices. However, to achieve targeted therapeutic purposes, complicated extractions, as well as modifications of exosomes, are involved. Here, based on the use of superparamagnetic iron oxide nanoparticles conjugated exosome (Ex-SPIONs), a facile exosome extraction through magnetism was established. The produced Ex-SPIONs exhibited a uniform size distribution and desirable biocompatibility. Moreover, taking advantage of the magnetic properties of SPIONs, the targeted delivery of Ex-SPIONs was demonstrated in the rat brain. Therefore, the constructed SPIONs functionalized exosome shows promising therapeutic potentials, including the treatment of brain diseases.     

Recent Progress in Transdermal Nanocarriers and Their Surface Modifications

Transdermal drug delivery system (TDDS) is an attractive method for drug delivery with convenient application, less first-pass effect, and fewer systemic side effects. Among all generations of TDDS, transdermal nanocarriers show the greatest clinical potential because of their non-invasive properties and high drug delivery efficiency. However, it is still difficult to design optimal transdermal nanocarriers to overcome the skin barrier, control drug release, and achieve targeting. Hence, surface modification becomes a promising strategy to optimize and functionalize the transdermal nanocarriers with enhanced penetration efficiency, controlled drug release profile, and targeting drug delivery. Therefore, this review summarizes the developed transdermal nanocarriers with their transdermal mechanism, and focuses on the surface modification strategies via their different functions.     

New advances in gated materials of mesoporous silica for drug controlled release

Drug delivery systems (DDS) are used to deliver therapeutic drugs to improve selectivity and reduce side effects. With the development of nanotechnology, many nanocarriers have been developed and applied to drug delivery, including mesoporous silica. Mesoporous silica nanoparticles (MSNs) have attracted a lot of attention for simple synthesis, biocompatibility, high surface area and pore volume. Based on the pore system and surface modification, gated mesoporous silica nanoparticles can be designed to realize on-command drug release, which provides a new approach for selective delivery of antitumor drugs. Herein, this review mainly focuses on the “gate keepers” of mesoporous silica for drug controlled release in nearly few years (2017–2020). We summarize the mechanism of drug controlled release in gated MSNs and different gated materials: inorganic gated materials, organic gated materials, self-gated drug molecules, and biological membranes. The facing challenges and future prospects of gated MSNs are discussed rationally in the end.     

Perylene-3-ylmethanol: fluorescent organic nanoparticles as a single-component photoresponsive nanocarrier with real-time monitoring of anticancer drug release

We report for the first time the use of perylene-3-ylmethanol fluorescent organic nanoparticles as a drug delivery system. In the present system, perylene-3-ylmethanol nanoparticles performed four important roles: (i) "nanocarriers" for drug delivery; (ii) "phototriggers" for the drug release; (iii) fluorescent chromophores for cell imaging; and (iv) detectors for real time-monitoring of drug release. In vitro biological studies revealed that the newly developed perylene-3-ylmethanol nanoparticles exhibit good biocompatibility and cellular uptake as well as efficient photoregulated anticancer drug release ability. Such fluorescent organic nanoparticles may open up new perspectives for designing a new class of promising photoresponsive nanocarriers for drug delivery.     

Biomedical and Pharmacological Uses of Fluorescein Isothiocyanate Chitosan‐Based Nanocarriers

Chitosan‐based nanocarriers (ChNCs) are considered suitable drug carriers due to their ability to encapsulate a variety of drugs and cross biological barriers to deliver the cargo to their target site. Fluorescein isothiocyanate‐labeled chitosan‐based NCs (FITC@ChNCs) are used extensively in biomedical and pharmacological applications. The main advantage of using FITC@ChNCs consists of the ability to track their fate both intra and extracellularly. This journey is strictly dependent on the physico‐chemical properties of the carrier and the cell types under investigation. Other applications make use of fluorescent ChNCs in cell labeling for the detection of disorders in vivo and controlling of living cells in situ. This review describes the use of FITC@ChNCs in the various applications with a focus on understanding their usefulness in labeled drug‐delivery systems.     

Tailoring nanocarriers for intracellular protein delivery

Proteins play a crucial role in life, taking part in all vital processes in the body. In the past decade, there was increasing interest in delivering active forms of proteins to specific cells and organs. Intracellular protein delivery holds enormous promise for biological and medical applications, including cancer therapy, vaccination, regenerative medicine, treatment for loss-of-function genetic diseases and imaging. This tutorial review surveys recent developments in intracellular protein delivery using various nanocarriers. Methods such as lipid-mediated colloidal systems, polymeric nanocarriers, inorganic systems and protein-mediated carriers are reviewed. Advantages and limitations of current strategies, as well as future opportunities and challenges are also discussed.     

Metal-Organic Frameworks Nanocarriers for Functional Nucleic Acid Delivery in Biomedical Applications

Metal−organic frameworks (MOFs), a distinctive funtionalmaterials which is constructed by various metal ions and organic molecules, have gradually attracted researchers′ attention from they were founded. In the last decade, MOFs emerge as a biomedical material with potential applications due to their unique properties. However, the MOFs performed as nanocarriers for functional nucleic acid delivery in biomedical applications rarely summarized. In this review, we introduce recent developments of MOFs for nucleic acid delivery in various biologically relevant applications, with special emphasis on cancer therapy (including siRNA, ASO, DNAzyme, miRNA and CpG oligodeoxynucleotides), bioimaging, biosensors and separation of biomolecules. We expect the accomplishment of this review could benefit certain researchers in biomedical field to develop novel sophisticated nanocarriers for functional nucleic acid delivery based on the promising material of MOFs.     

葡萄糖敏感苯硼酸基高分子纳米药物传输体系

近年来,智能葡萄糖敏感自调式药物传递系统备受关注。这种智能药物释放系统能够模拟胰腺分泌胰岛素的生理模式而精准调控药物释放并控制血糖水平,在糖尿病治疗中具有良好的应用前景。其中,苯硼酸(PBA)功能化的葡萄糖敏感高分子纳米载体成为近年来的研究热点之一。该类材料具有体系稳定、可长期储存、可逆的葡萄糖敏感性能等优势。根据响应因素不同,葡萄糖敏感药物传递系统可分为pH响应、温度响应和光响应等类型。本文重点介绍了基于PBA的葡萄糖敏感高分子纳米药物载体的发展过程、性能和应用,并对该领域的发展前景进行了展望。     

Advances in lipid carriers for drug delivery to the gastrointestinal tract

Lipid-based formulations have re-emerged as oral drug delivery systems. Advances in the techniques to evaluate the in vivo fate of the formulations, together with an improved knowledge of the gastrointestinal processes/barriers to the evolving lipid-based systems, could explain, at least partially, this revival. In addition, the use of lipid-based formulations is no longer limited to highly lipophilic drugs and has been extended to hydrophilic peptides and macromolecules. Last but not least, (targeted) nanocarriers have been developed exploiting gut physiology toward novel targets in the field. We herein review what we believe have been the major advances in oral drug delivery via lipid-based formulations in recent years, leading to their re-emergence as promising drug delivery systems for future clinical application.     

Environment-Recognizing DNA-Computation Circuits for the Intracellular Transport of Molecular Payloads for mRNA Imaging

Programming intelligent DNA nanocarriers for the targeted transport of molecular payloads in living cells has attracted extensive attention. In vivo activation of these nanocarriers usually relies on external light irradiation. An interest is emerging in the automatic recognition of intracellular surroundings by nanocarriers and their in situ activation under the control of programmed DNA-computation circuits. Herein, we report the integration of DNA circuits with framework nucleic acid (FNA) nanocarriers that consist of a truncated square pyramid (TSP) cage and a built-in duplex cargo containing an antisense strand of the target mRNA. An i-motif and ATP aptamer embedded in the TSP are employed as logic-controlling units to respond to H⁺ and ATP inside cellular compartments, triggering the release of the sensing element for fluorescent mRNA imaging. Logic-controlled FNA devices could be used to target drug delivery, enabling precise disease treatment.     

Harnessing the full potential of extracellular vesicles as drug carriers

Extracellular vesicles are natural delivery systems widely implicated in cellular communication. However, to fully utilize these vehicles as nanocarriers, we must explore various methods to modify their applicability as drug delivery vehicles. In this review, we outline and discuss techniques to engineer extracellular vehicles for enhanced loading, targeting, circulation, and tracking. We highlight cutting-edge methods to amplify extracellular vesicle secretion and production and optimize storage conditions to improve their clinical suitability. Moreover, we focus on reverse engineering as an important step in controlling their biological function. By taking a reductionist approach to characterize and understand the individual components of these carriers, we can not only elucidate complex mechanisms of action but also advance the field through the creation of synthetic drug delivery vehicles. Finally, we propose current challenges and future directions of the field.