Supramolecular Nanoparticles of Histone and Hyaluronic Acid for Co-Delivery of siRNA and Photosensitizer In Vitro.

Small interfering RNA (siRNA) has significant potential as a treatment for cancer by targeting specific genes or molecular pathways involved in cancer development and progression. The addition of siRNA to other therapeutic strategies, like photodynamic therapy (PDT), can enhance the anticancer effects, providing synergistic benefits. Nevertheless, the effective delivery of siRNA into target cells remains an obstacle in cancer therapy. Herein, supramolecular nanoparticles were fabricated via the co-assembly of natural histone and hyaluronic acid for the co-delivery of HMGB1-siRNA and the photosensitizer chlorin e6 (Ce6) into the MCF-7 cell. The produced siRNA-Ce6 nanoparticles (siRNA-Ce6 NPs) have a spherical morphology and exhibit uniform distribution. In vitro experiments demonstrate that the siRNA-Ce6 NPs display good biocompatibility, enhanced cellular uptake, and improved cytotoxicity. These outcomes indicate that the nanoparticles constructed by the co-assembly of histone and hyaluronic acid hold enormous promise as a means of siRNA and photosensitizer co-delivery towards synergetic therapy.

Supramolecular Nanoarchitectonics Based on Antagonist Peptide Self-Assembly for Treatment of Liver Fibrosis.

Therapeutic peptides have attracted increasing attention as anti-fibrotic drug candidates. However, the rapid degradation and insufficient liver accumulation of therapeutic peptides have seriously hampered their clinical translation. Here, the use of supramolecular nanoarchitectonics is reported to fabricate nanodrugs from therapeutic peptides for treating liver fibrosis. Self-assembling antagonist peptides are rationally designed and manipulated into uniform peptide nanoparticles with well-defined nanostructures and uniform sizes. Significantly, the peptide nanoparticles show enhanced accumulation in liver sites and limited distribution in other tissues. In vivo results show that the peptide nanoparticles exhibit greatly enhanced anti-fibrotic activity compared to the pristine antagonist along with good biocompatibility. These results indicate that self-assembly is a promising nanoarchitectonics approach to enhance the anti-fibrotic activity of therapeutic peptides for treating liver fibrosis.

Peptide-Based Nanoarchitectonics for the Treatment of Liver Fibrosis.

Liver fibrosis is a process of excessive accumulation of extracellular matrix caused by liver injury. Liver fibrosis can progress to cirrhosis or even liver cancer without proper intervention. Until now, no effective therapeutic drugs have been clinically approved for treating liver fibrosis. Hence, the development of safe and effective antifibrotic drugs is particularly important. As a representative biomaterial, peptides have been investigated as key components for constructing antifibrotic nanomaterials given their advantages of biological origination, synthetic availability, and good biocompatibility. Peptides serve as multifunctional motifs in antifibrotic nanomaterials, such as liver-targeting molecules, antifibrotic molecules, and self-assembling building blocks for the formation of the nanomaterials. In this review, we focus on peptide-based nanoarchitectonics for treating liver fibrosis, including nanomaterials modified with liver-targeting peptides, nanomaterials for the efficient delivery of antifibrotic peptides, and self-assembled peptide nanomaterials for the delivery of antifibrotic drugs. The design rules of these peptide-based nanomaterials are described. The antifibrotic mechanisms and effects of these peptide-based nanomaterials in treating liver fibrosis and related diseases are highlighted. The challenges and future perspectives of using peptide-based nanoarchitectonics for the treatment of liver fibrosis are discussed. These results are expected to accelerate the rational design and clinical translation of antifibrotic nanomaterials.

Novel active stealth micelles based on ß2M achieved effective antitumor therapy.

Micelles have been extensively investigated as drug delivery systems for loading of antitumor drugs with the advantages of good dispersibility, controllable size distribution, and high loading capacity. However, phagocytic clearance by the mononuclear phagocyte system remains a major impediment that inhibits blood circulation and thus tumor accumulation of micelles. Inspired by the antiphagocytic properties of ß2-microglobulin (ß2M), here we developed a ß2M-derived peptide for the surface functionalization of micelles. A ß2M-derived sequence was integrated with a matrix metalloproteinase-2 (MMP-2) cleavable sequence and then modified on the surface of poly(ethylene glycol)-b-poly(caprolactone) (PEG-PCL) micelles, endowing the micelles with both antiphagocytic and MMP-2-responsive properties. Compared to pristine PEG-PCL micelles, micelles modified with the dual-functional peptide exhibited higher inhibition of phagocytosis by macrophages in the absence of MMP-2, and enhanced internalization by tumor-associated macrophages in the presence of MMP-2, leading to enhanced tumor accumulation of the loaded photosensitizer, thus enabling antitumor therapy. These results demonstrated that antiphagocytic peptides derived from endogenous proteins are promising for functionalization of micelles in smart drug delivery.

Functional Nanomaterials Based on Self-Assembly of Endogenic NIR-Absorbing Pigments for Diagnostic and Therapeutic Applications.

Endogenic pigments derived from hemoglobin have been successfully applied in the clinic for both imaging and therapy based on their inherent photophysical and photochemical properties, including light absorption, fluorescence emission, and producing reactive oxygen species. However, the clinically approved endogenic pigments can be excited only by UV/vis light, restricting the penetration depth of in vivo applications. Recently, endogenic pigments with NIR-absorbing properties have been explored for constructing functional nanomaterials. Here, the overview of NIR-absorbing endogenic pigments, mainly bile pigments, and melanins, as emerging building blocks for supramolecular construction of diagnostic and therapeutic nanomaterials is provided. The endogenic origins, synthetic pathways, and structural characteristics of the NIR-absorbing endogenic pigments are described. The self-assembling approaches and noncovalent interactions in fabricating the nanomaterials are emphasized. Since bile pigments and melanins are inherently photothermal agents, the resulting nanomaterials are demonstrated as promising candidates for photoacoustic imaging and photothermal therapy. Integration of additional diagnostic and therapeutic agents by the nanomaterials through chemical conjugation or physical encapsulation toward synergetic effects is also included. Especially, the degradation behaviors of the nanomaterials in biological environments are summarized. Along with the challenges, future perspectives are discussed for accelerating the ration design and clinical translation of NIR-absorbing nanomaterials.

Amino-Acid-Encoded Supramolecular Photothermal Nanomedicine for Enhanced Cancer Therapy.

Photothermal nanomedicine based on self-assembly of biological components, with excellent biosafety and customized performance, is vital significance for precision cancer therapy. However, the programmable design of photothermal nanomedicine remains extremely challenging due to the vulnerability and variability of noncovalent interactions governing supramolecular self-assembly. Herein, it is reported that amino acid encoding is a facile and potent means to design and construct supramolecular photothermal nanodrugs with controlled therapeutic activities. It is found that the amount and type of amino acid dominates the assembled nanostructures, structural stability, energy-conversion pathway, and therapeutic mechanism of the resulting nanodrugs. Two optimized nanodrugs are endowed with robust structural integrity against disassembly along with high photothermal conversion efficiency, efficient cellular internalization, and enhanced tumor accumulation, which result in more efficient tumor ablation. This work demonstrates that design based on amino acid encoding offers an unprecedented opportunity for the construction of remarkable photoactive nanomedicines toward cancer diagnostics and therapeutics.

Self-assembly of amino acids toward functional biomaterials.

Biomolecules, such as proteins and peptides, can be self-assembled. They are widely distributed, easy to obtain, and biocompatible. However, the self-assembly of proteins and peptides has disadvantages, such as difficulty in obtaining high quantities of materials, high cost, polydispersity, and purification limitations. The difficulties in using proteins and peptides as functional materials make it more complicate to arrange assembled nanostructures at both microscopic and macroscopic scales. Amino acids, as the smallest constituent of proteins and the smallest constituent in the bottom-up approach, are the smallest building blocks that can be self-assembled. The self-assembly of single amino acids has the advantages of low synthesis cost, simple modeling, excellent biocompatibility and biodegradability in vivo. In addition, amino acids can be assembled with other components to meet multiple scientific needs. However, using these simple building blocks to design attractive materials remains a challenge due to the simplicity of the amino acids. Most of the review articles about self-assembly focus on large molecules, such as peptides and proteins. The preparation of complicated materials by self-assembly of amino acids has not yet been evaluated. Therefore, it is of great significance to systematically summarize the literature of amino acid self-assembly. This article reviews the recent advances in amino acid self-assembly regarding amino acid self-assembly, functional amino acid self-assembly, amino acid coordination self-assembly, and amino acid regulatory functional molecule self-assembly.

Supramolecular Nanodrugs Based on Covalent Assembly of Therapeutic Peptides toward In Vitro Synergistic Anticancer Therapy.

Therapeutic peptides have attracted significant attention in clinical applications due to their advantages in biological origination and good biocompatibility. However, the therapeutic performance of peptides is usually hindered by their short half-lives in blood and inferior activity. Herein, supramolecular nanodrugs of therapeutic peptides are constructed by covalent assembly of chemotherapeutic peptides through genipin cross-linking. The resulting nanodrugs have intense absorbance in the near-infrared region and high photothermal conversion efficiencies, leading to the possibility of photothermal therapy. The combination of photothermal therapy and chemotherapy using the nanodrugs shows synergistic therapeutic effects on cancer cells. Hence, covalent assembly not only maintains the chemotherapeutic activities of the peptides but also triggers supramolecular photothermal effects, demonstrating that the covalent assembly of therapeutic peptides through genipin cross-linking is an efficient approach in constructing supramolecular nanodrugs toward synergistic anticancer therapy.

Biomimetic Nanozymes Based on Coassembly of Amino Acid and Hemin for Catalytic Oxidation and Sensing of Biomolecules.

Nanoassemblies based on self-assembly of biological building blocks are promising in mimicking the nanostructures, properties, and functionalities of natural enzymes. However, it remains a challenge to design of biomimetic nanozymes with tunable nanostructures and enhanced catalytic activities starting from simple biomolecules. Herein, the construction of nanoassemblies through coassembly of an amphiphilic amino acid and hemin is reported. The nanostructures and morphologies of the resulting nanoassemblies are readily controlled by tuning the molar ratio between the amino acid and hemin, thus leading to tailored peroxidase-mimicking activities of the nanoassemblies. Importantly, the optimized nanoassemblies exhibit a remarkable catalytic efficiency that is comparable to the natural counterpart when considering molecular mass along with good robustness in multiple catalytic cycles. The nanoassemblies are effectively integrated as biomimetic nanozymes in a sensing system for catalytic detection of glucose. Therefore, this work demonstrates that nanozymes with advanced catalytic capabilities can be constructed by self-assembly of minimalist biological building blocks and may thus promote the rational design and catalytic applications of biomimetic nanozymes.

Porphyrin/Ionic-Liquid Co-assembly Polymorphism Controlled by Liquid-Liquid Phase Separation.

Understanding and controlling multicomponent co-assembly is of primary importance in different fields, such as materials fabrication, pharmaceutical polymorphism, and supramolecular polymerization, but these aspects have been a long-standing challenge. Herein, we discover that liquid-liquid phase separation (LLPS) into ion-cluster-rich and ion-cluster-poor liquid phases is the first step prior to co-assembly nucleation based on a model system of water-soluble porphyrin and ionic liquids. The LLPS-formed droplets serve as the nucleation precursors, which determine the resulting structures and properties of co-assemblies. Co-assembly polymorphism and tunable supramolecular phase transition behaviors can be achieved by regulating the intermolecular interactions at the LLPS stage. These findings elucidate the key role of LLPS in multicomponent co-assembly evolution and enable it to be an effective strategy to control co-assembly polymorphism as well as supramolecular phase transitions.

Self-Assembling Proteins for Design of Anticancer Nanodrugs.

Inspired by the diverse protein-based structures and materials in organisms, proteins have been expected as promising biological components for constructing nanomaterials toward various applications. In numerous studies protein-based nanomaterials have been constructed with the merits of abundant bioactivity and good biocompatibility. However, self-assembly of proteins as a dominant approach in constructing anticancer nanodrugs has not been reviewed. Here, we provide a comprehensive account of the role of protein self-assembly in fabrication, regulation, and application of anticancer nanodrugs. The supramolecular strategies, building blocks, and molecular interactions of protein self-assembly as well as the properties, functions, and applications of the resulting nanodrugs are discussed. The applications in chemotherapy, radiotherapy, photodynamic therapy, photothermal therapy, gene therapy, and combination therapy are included. Especially, manipulation of molecular interactions for realizing cancer-specific response and cancer theranostics are emphasized. By expounding the impact of molecular interactions on therapeutic activity, rational design of highly efficient protein-based nanodrugs for precision anticancer therapy can be envisioned. Also, the challenges and perspectives in constructing nanodrugs based on protein self-assembly are presented to advance clinical translation of protein-based nanodrugs and next-generation nanomedicine.

Injectable self-assembled bola-dipeptide hydrogels for sustained photodynamic prodrug delivery and enhanced tumor therapy.

Supramolecular peptide materials have attracted increasing attention due to their natural biological origin and versatile applications. However, it is often challenging to control and modulate the self-assembly of peptides (especially short peptides) for constructing hydrogels with tunable mechanical properties and adaptive injectability toward biomedical applications. Here, we report a supramolecular strategy for forming robust and injectable hydrogels based on the self-assembly of a rationally designed bola-dipeptide. The self-assembled hydrogels exhibit versatile functionalities, including flow under shear stress, good recovery properties, and easy encapsulation of hydrophilic prodrugs. The prodrug-loaded hydrogels show sustained release profiles, inhibited nontargeted leakage, and enhanced localized prodrug conversion, leading to highly efficient photodynamic tumor ablation. Hence, the supramolecular strategy is promising for the rational construction of injectable hydrogels toward targeted and sustained prodrug conversion and tumor therapy.

Supramolecular Nanodrugs Constructed by Self-Assembly of Peptide Nucleic Acid-Photosensitizer Conjugates for Photodynamic Therapy.

Two hybrid materials were designed by conjugating peptide nucleic acids (PNAs) to porphyrin or boron-dipyrromethene, generating PNA-porphyrin (PNA-TPP) and PNA-BODIPY (PNA-BDP) conjugates, respectively. Because of the combination of the supramolecular characteristics of PNAs and photosensitizers, the two hybrid conjugates readily self-assemble in aqueous solutions and produce well-defined nanoparticles with uniform particle sizes. The resulting two kinds of nanoparticles show good stability in biological solutions and upon dilution. Importantly, the nanoparticles can efficiently interact with cancer cells and the internalized nanoparticles are mainly distributed in the cytoplasm without discernible cytotoxicity in the dark, enabling them to be applied as photodynamic nanoagents for selective killing cells. Hence, self-assembly of PNA-photosensitizer conjugates may hold promise for advancing the rational design and construction of photodynamic nanoagents for cancer therapy.

Self-assembled injectable biomolecular hydrogels towards phototherapy.

Biomolecular hydrogels assembled from biomolecules, such as proteins, peptides, and polysaccharides, are promising candidates for facilitating biomedical applications due to their advantages of high biocompatibility, adjustable mechanical properties, functional diversity, and good degradability. This review focuses on current progress in the field of supramolecular injectable biomolecular hydrogels and their applications in antitumor photodynamic therapy (PDT), photothermal therapy (PTT), combined PDT and PTT, and antibacterial phototherapy with emphasis on biomolecular hydrogelators, injectable behaviors, phototherapeutic functions, and the remaining challenges. We hope that this review can provide useful inspiration for the construction and biological applications of novel photo-functional hydrogels as well as phototherapies.

Supramolecular Protein Nanodrugs with Coordination- and Heating-Enhanced Photothermal Effects for Antitumor Therapy.

Supramolecular protein nanodrugs provide opportunities for improving antitumor therapeutic efficiency and lowering toxicity. However, protein nanodrugs that have robust structural stability and enhanced therapeutic efficiency are still in infancy. In this study, photothermal protein nanodrugs are constructed through a supramolecular approach along with heating by using proteins, photosensitizers, and metal ions as the building blocks. The metal coordination and heating improve not only the structural stability but also photothermal performance of the resulting nanodrugs. By virtue of the first integration of coordination- and heating-enhanced photothermal effects, the nanodrugs show superior photothermal conversion efficiency, enhanced tumor accumulation, and improved tumor inhibition. Metal coordination and heating are versatile to be applied for various protein nanodrugs. Hence, this study provides insights for the construction of highly efficient photothermal nanodrugs and thus will be beneficial to precision theranostics.

Robust Photothermal Nanodrugs Based on Covalent Assembly of Nonpigmented Biomolecules for Antitumor Therapy.

Photothermal nanodrugs based on biomolecules are critically important for advancing photothermal therapy (PTT). However, constructing photothermal nanodrugs from biomolecules is highly challenging because most biomolecules are inherently nonpigmented. Herein, we synthesize well-defined, uniform photothermal nanodrugs through a covalent assembly approach by using nonpigmented peptides and iridoids as building blocks. The resulting photothermal nanodrugs show broad absorption from the UV to the near-infrared region, high photothermal conversion efficiency along with robust photostability, and selective tumor accumulation, leading to highly efficient tumor ablation via PTT. This work represents the first example of photothermal nanodrugs that can be constructed by using nonpigmented biomolecules as building blocks and thus will conceivably promote the preclinical evaluation and clinical translation of PTT.

High-tolerance crystalline hydrogels formed from self-assembling cyclic dipeptide.

Peptide-based supramolecular hydrogels, as a new type of biological nanoarchitectonic structure, hold great promise for a wide range of biomedical and nanotechnological applications, such as tissue engineering, drug delivery, and electronic and photonic energy storage. In this work, a cyclic dipeptide (CDP) cyclo-(Trp-Tyr) (C-WY), which has exceptional structural rigidity and high stability, is selected as a hydrogelator for the formation of supramolecular hydrogels. The unique hydrogen bonding in C-WY endows a high propensity for self-assembly and the resulting hydrogels are revealed to be crystalline. The crystalline hydrogels possess excellent mechanical capacity and superior tolerance to various harsh conditions, including in the presence of charged biopolymers, extreme acid/base environments, and changing thermal conditions. Such high tolerance enables the crystalline hydrogels to be applied in the complex and harsh environments of electrochemistry. In addition, this study demonstrates that the self-assembly of cyclic dipeptides results in highly robust hydrogels which can be applied for electrochemical applications such as electrochemical supercapacitors.

Nucleation and Growth of Amino Acid and Peptide Supramolecular Polymers through Liquid-Liquid Phase Separation.

The transition of peptides and proteins from the solution phase into fibrillar structures is a general phenomenon encountered in functional and aberrant biology and is increasingly exploited in soft materials science. However, the fundamental molecular events underpinning the early stages of their assembly and subsequent growth have remained challenging to elucidate. Here, we show that liquid-liquid phase separation into solute-rich and solute-poor phases is a fundamental step leading to the nucleation of supramolecular nanofibrils from molecular building blocks, including peptides and even amphiphilic amino acids. The solute-rich liquid droplets act as nucleation sites, allowing the formation of thermodynamically favorable nanofibrils following Ostwald's step rule. The transition from solution to liquid droplets is entropy driven while the transition from liquid droplets to nanofibrils is mediated by enthalpic interactions and characterized by structural reorganization. These findings shed light on how the nucleation barrier toward the formation of solid phases can be lowered through a kinetic mechanism which proceeds through a metastable liquid phase.

Photoactive properties of supramolecular assembled short peptides.

Bioinspired nanostructures can be the ideal functional smart materials to bridge the fundamental biology, biomedicine and nanobiotechnology fields. Among them, short peptides are among the most preferred building blocks as they can self-assemble to form versatile supramolecular architectures displaying unique physical and chemical properties, including intriguing optical features. Herein, we discuss the progress made over the past few decades in the design and characterization of optical short peptide nanomaterials, focusing on their intrinsic photoluminescent and waveguiding performances, along with the diverse modulation strategies. We review the complicated optical properties and the advanced applications of photoactive short peptide self-assemblies, including photocatalysis, as well as photothermal and photodynamic therapy. The diverse advantages of photoactive short peptide self-assemblies, such as eco-friendliness, morphological and functional flexibility, and ease of preparation and modification, endow them with the capability to potentially serve as next-generation, bio-organic optical materials, allowing the bridging of the optics world and the nanobiotechnology field.

Peptide-modulated self-assembly as a versatile strategy for tumor supramolecular nanotheranostics.

Advances in supramolecular self-assembly have promoted the development of theranostics, the combination of both therapeutic and diagnostic functions in a single nanoplatform, which is closely associated with antitumor applications and has shown promising potential in personalized medicine. Peptide-modulated self-assembly serves as a versatile strategy for tumor supramolecular nanotheranostics possessing controllability, programmability, functionality and biosafety, thus promoting the translation of nanotheranostics from bench to bedside. In this review, we will focus on the self-assembly of peptide-photosensitizers and peptide-drugs as well as multicomponent cooperative self-assembly for the fabrication of nanotheranostics that integrate diagnosis and therapeutics for antitumor applications. Emphasis will be placed on building block design, interaction strategies and the potential relationships between their structures and properties, aiming to increase understanding of the critical role of peptide-modulated self-assembly in advancing antitumor supramolecular nanotheranostics.