The delivery of proteins into cells is a potential game changer for a wide array of therapeutic purposes, including cancer therapy, immunomodulation and treatment of inherited diseases. In this ...review, we present recently developed nanoassemblies for protein delivery that utilize strategies that range from direct assembly, encapsulation and composite formation. We will discuss factors that affect the efficacy of nanoassemblies for delivery from the perspective of both nanoparticles and proteins. Challenges in the field, particularly achieving effective cytosolar protein delivery through endosomal escape or evasion are discussed.
Direct intracellular delivery of proteins using inorganic nanoparticle-protein supramolecular assemblies.
Stimuli-responsive hydrogels are intriguing biomaterials useful for spatiotemporal controlled release of drugs, cells, and biological cues, cell engineering for various applications, and medical ...diagnosis. To date, many physical and chemical stimuli-responsive polymer hydrogels have been developed by chemical modification of polymer chains and cross-linking points. In particular, conjugation with biomolecules to polymers produced promising biomolecule-responsive hydrogels. These examples clearly indicate high potentials of stimuli-responsive hydrogels as promising biomaterials. In addition to polymer hydrogels, supramolecular hydrogels formed by the assembly of small molecules (hydrogelators) via noncovalent interactions have also been regarded as unique and promising soft materials due to their flexible programmability in rendering them stimuli-responsive with the larger macroscopic change (i.e., gel–sol transition). This Account describes our strategies for the rational design of stimuli-responsive supramolecular hydrogels and their biological applications. Following the detailed structural analysis of a lead hydrogelator that clearly indicates the appropriate sites for incorporation of stimuli-responsive modules, we designed supramolecular hydrogels capable of responding to simple physical (thermal and light) and chemical (pH and metal ions) stimuli. More importantly, biomolecule-responsive hydrogels were successfully developed by supramolecularly mimicking the complex yet well-ordered structures and functions of live cells containing multiple components (a cell-mimicking approach). Development of biomolecule-responsive supramolecular hydrogels has been difficult as the conventional strategy relies on the chemical incorporation of stimuli-responsive modules, owing to the lack of modules that can effectively respond to structurally diverse and complicated biomolecules. Inspired by natural systems where functional compartments (e.g., cell organelles) sophisticatedly interact with each other, we sought to integrate the two distinct microenvironments of supramolecular hydrogels (the aqueous cavity surrounded by fibers and the fluidic hydrophobic fiber domain) with other functional materials (e.g., enzymes, peptides or proteins, fluorescent chemosensors, or inorganic porous or layered nanomaterials) for biomolecule responses. In situ fluorescence microscopy imaging clearly demonstrated that chemical isolation and crosstalk are highly successful between the integrated microenvironments in supramolecular hydrogels, similar to organelles in living cells, which allow for the construction of unique optical response and sensing systems for biomolecules. Furthermore, programmed hybridization of our chemically reactive hydrogels with appropriate enzymes can provide an unprecedented universal platform for biomolecule-degradable supramolecular hydrogels. Such biomolecule-responsive hydrogels are a potentially promising tool for user-friendly early diagnostics and on-demand drug-releasing soft materials. We expect that our rational design strategies for stimuli-responsive supramolecular hydrogels by modification of chemical structures and hybridization with functional materials will inspire scientists in various fields and lead to development of novel soft materials for biological applications.
The rational design of drug delivery approaches leveraging supramolecular chemistry (
i.e.
, "
chemistry beyond the molecule
") has garnered significant interest in recent years toward improving ...therapeutics. By using specific, dynamic, and tunable non-covalent interactions, engineered approaches to drug delivery can be realized. Certain benefits to this approach are molecular-level control of composition, improved routes for incorporating and targeting drugs, and new strategies to create delivery devices that respond to a variety of physiologic indicators. Some of the most recognizable supramolecular motifs - macrocyclic host-guest complexes - afford logical application to drug delivery in using drug as guest. The use of supramolecular motifs may further give rise to materials for the controlled encapsulation and release of therapeutics. Furthermore, given the majority of supramolecular motifs in water are directed by hydrophobic interactions, cooperative delivery strategies can be realized. The modularity of supramolecular interactions also facilitates opportunities to combine multiple drugs within one delivery platform, as well as the facile incorporation of targeting units. In sum, supramolecular design offers ample opportunity to improve the precision of pharmaceutical practice. In the context of clinical translation, features of supramolecular design may prove additionally advantageous, specifically in enabling quantitative drug loading, molecularly discrete delivery devices, and
a priori
knowledge of carrier degradation and clearance mechanisms. As such, the design opportunities afforded by supramolecular chemistry will play a vital role in the future of the drug delivery field.
Principles rooted in supramolecular chemistry have empowered new and highly functional therapeutics and drug delivery devices. This general approach offers elegant tools rooted in molecular and materials engineered to address the many challenges faced in treating disease.
Supramolecular medicine Cui, Honggang; Xu, Bing
Chemical Society reviews,
10/2017, Letnik:
46, Številka:
21
Journal Article
Recenzirano
Guest editors Honggang Cui and Bing Xu introduce the supramolecular medicine issue of
Chemical Society Reviews
. In a broader context,
Supramolecular Medicine
can be defined as the supramolecular ...formulation of diagnostic and therapeutic agents for the diagnosis, treatment, and prevention of disease.
In order to develop better wound dressings, a novel chitosan hydrogel (Cn-Nm gel) was designed and fabricated by using aldehyde-4-arm polyethylene glycol (4r-PEG-CHO) to crosslink the chitosan ...dissolved in alkaline solution, amino-4-arm polyethylene glycol (4r-PEG-NH2) was chosen as the additive simultaneously. The special dissolution technique and macromolecular crosslinking structure endows the Cn-Nm gels with better performance than that of gels prepared by acid dissolving method with micromolecule crosslinker. First, Cn-Nm gels own strong toughness with 500 kPa tensile strength and 1000% elongation, about 400% swelling ratio and fast water absorption rate. Second, about 300 kPa adhesive strength and strippability between the gels and skin is achieved. More importantly, Cn-Nm gels show nearly 100% antibacterial rate towards Escherichia coli and Staphylococcus aureus. Excellent biocompatibility is also proved by the mouse fibroblasts tests. All of the performance makes this developed chitosan-based gel be the potential candidate as a wound dressing.
Synthetic assembly within living cells represents an innovative way to explore purely chemical tools that can direct and control cellular behavior. We use a simple and modular platform that is ...broadly accessible and yet incorporates highly intricate molecular recognition, immolative, and rearrangement chemistry. Short bimodular peptide sequences undergo a programmed sequence of events that can be tailored within the living intracellular environment. Each sequential stage of the pathways beginning with the cellular uptake, intracellular transport, and localization imposes distinct structural changes that result in the assembly of fibrillar architectures inside cells. The observation of apoptosis, which is characterized by the binding of Annexin V, demonstrates that programmed cell death can be promoted by the peptide assembly. Higher complexity of the assemblies was also achieved by coassembly of two different sequences, resulting in intrinsically fluorescent architectures. As such, we demonstrate that the in situ construction of architectures within cells will broaden the community’s perspective toward how structure formation can impact a living system.
Supramolecular systems have applications in areas as diverse as materials science, biochemistry, analytical chemistry, and nanomedicine. However, analyzing such systems can be challenging due to the ...wide range of time scales, binding strengths, distances, and concentrations at which non-covalent phenomena take place. Due to their versatility and sensitivity, Förster resonance energy transfer (FRET)-based techniques are excellently suited to meet such challenges. Here, we detail the ways in which FRET has been used to study non-covalent interactions in both synthetic and biological supramolecular systems. Among other topics, we examine methods to measure molecular forces, determine protein conformations, monitor assembly kinetics, and visualize
in vivo
drug release from nanoparticles. Furthermore, we highlight multiplex FRET techniques, discuss the field's limitations, and provide a perspective on new developments.
This review details the ways Förster resonance energy transfer (FRET) can be used to study natural and synthetic supramolecular systems.
Extracellular matrix (ECM) provides essential supports three dimensionally to the cells in living organs, including mechanical support and signal, nutrition, oxygen, and waste transportation. Thus, ...using hydrogels to mimic its function has attracted much attention in recent years, especially in tissue engineering, cell biology, and drug screening. However, a hydrogel system that can merit all parameters of the natural ECM is still a challenge. In the past decade, deoxyribonucleic acid (DNA) has arisen as an outstanding building material for the hydrogels, as it has unique properties compared to most synthetic or natural polymers, such as sequence designability, precise recognition, structural rigidity, and minimal toxicity. By simple attachment to polymers as a side chain, DNA has been widely used as cross-links in hydrogel preparation. The formed secondary structures could confer on the hydrogel designable responsiveness, such as response to temperature, pH, metal ions, proteins, DNA, RNA, and small signal molecules like ATP. Moreover, single or multiple DNA restriction enzyme sites could be incorporated into the hydrogels by sequence design and greatly expand the latitude of their responses. Compared with most supramolecular hydrogels, these DNA cross-linked hydrogels could be relatively strong and easily adjustable via sequence variation, but it is noteworthy that these hydrogels still have excellent thixotropic properties and could be easily injected through a needle. In addition, the quick formation of duplex has also enabled the multilayer three-dimensional injection printing of living cells with the hydrogel as matrix. When the matrix is built purely by DNA assembly structures, the hydrogel inherits all the previously described characteristics; however, the long persistence length of DNA structures excluded the small size meshes of the network and made the hydrogel permeable to nutrition for cell proliferation. This unique property greatly expands the cell viability in the three-dimensional matrix to several weeks and also provides an easy way to prepare interpenetrating double network materials. In this Account, we outline the stream of hydrogels based on DNA self-assembly and discuss the mechanism that brings outstanding properties to the materials. Unlike most reported hydrogel systems, the all-in-one character of the DNA hydrogel avoids the “cask effect” in the properties. We believe the hydrogel will greatly benefit cell behavior studies especially in the following aspects: (1) stem cell differentiation can be studied with solely tunable mechanical strength of the matrix; (2) the dynamic nature of the network can allow cell migration through the hydrogel, which will help to build a more realistic model to observe the migration of cancer cells in vivo; (3) combination with rapidly developing three-dimension printing technology, the hydrogel will boost the construction of three-dimensional tissues and artificial organs.
In this review, supramolecular catalysis refers to the integration of the catalytic process with molecular self-assembly driven by noncovalent interactions, and dynamic assemblies are the assemblies ...that form and dissipate reversibly. Cells extensively employ supramolecular catalysis and dynamic assemblies for controlling their complex functions. The dynamic generation of supramolecular assemblies of small molecules has made considerable progress in the last decade, though the disassembly processes remain underexplored. Here, we discuss the regulation of dynamic assemblies
via
self-assembly and disassembly processes for therapeutics and diagnostics. We first briefly introduce the self-assembly and disassembly processes in the context of cells, which provide the rationale for designing approaches to control the assemblies. Then, we describe recent advances in designing and regulating the self-assembly and disassembly of small molecules, especially for molecular imaging and anticancer therapeutics. Finally, we provide a perspective on future directions of the research on supramolecular catalysis and dynamic assemblies for medicine.
This review provides new insights into supramolecular catalysis and dynamic regulation of molecular assemblies for biomedical applications.
PDF
