Smart Biomaterials: Recent Advances and Future Directions

Kowalski, Piotr S.; Bhattacharya, Chandrabali; Afewerki, Samson; Langer, Robert

doi:10.1021/acsbiomaterials.8b00889

Cited by 148 publications

(110 citation statements)

References 94 publications

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“…Following a similar trend as seen with siRNA carriers, new biodegradable polymers with biocompatible degradation products and enhanced endosomal escape capabilities are expected to emerge for mRNA delivery, which may facilitate clinical translation of these materials. 70 Dendrimers. Polyamidoamine (PAMAM) or polypropyleniminebased dendrimers have been extensively studied for gene delivery.…”

Section: Reviewmentioning

confidence: 99%

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

et al. 2019

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mRNA has broad potential as a therapeutic. Current clinical efforts are focused on vaccination, protein replacement therapies, and treatment of genetic diseases. The clinical translation of mRNA therapeutics has been made possible through advances in the design of mRNA manufacturing and intracellular delivery methods. However, broad application of mRNA is still limited by the need for improved delivery systems. In this review, we discuss the challenges for clinical translation of mRNA-based therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. mRNA holds the potential to revolutionize vaccination, protein replacement therapies, and the treatment of genetic diseases. Since the first pre-clinical studies in the 1990s, 1 significant progress in the clinical translation of mRNA therapeutics has been made through advances in the design of mRNA manufacturing and intracellular delivery methods. 2 The translatability and stability of mRNA as well as its immunostimulatory activity are the key factors to be optimized for specific therapeutic application. 3 Increased translation and stability can be affected by many regions of the RNA. mRNA 5 0 and 3 0 UTRs are responsible for recruiting RNA-binding proteins and microRNAs, and they can profoundly affect translational activity. 2,4 The modification of rare codons in protein-coding sequences with synonymous frequently occurring codons, so-called codon optimization, can result in order-of-magnitude changes in expression levels. 5,6 Modification of the 5 0 mRNA cap can also enhance mRNA translation by inhibiting RNA decapping and improving resistance to enzymatic degradation. 7 Chemical modification of RNA bases can be used to modify mRNA immunostimulatory activity. 8,9 The importance of immunostimulation can depend on the application, 10 and, in some cases, it may actually improve performance, as in the case of vaccines. 11Finally, methods and vehicles for intracellular delivery remain the major barrier to the broad application of mRNA therapeutics. 12 With some exceptions, the intracellular delivery of mRNA is generally more challenging than that of small oligonucleotides, and it requires encapsulation into a delivery nanoparticle, in part due to the significantly larger size of mRNA molecules (300-5,000 kDa, 1-15 kb) as compared to other types of RNAs (small interfering RNAs [siRNAs], 14 kDa; antisense oligonucleotides [ASOs], 4-10 kDa). 10,13 In this review, we discuss the challenges for clinical translation of mRNAbased therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. Materials for mRNA Delivery Structural Aspects of Material DesignAmong the many barriers to function, mRNA must cross the cell membrane in order to reach the cytoplasm (Figure 1). The cell me...

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Section: Reviewmentioning

confidence: 99%

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

et al. 2019

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“…[23][24][25]30,33 Cationic poly(b-aminoester)s have demonstrated good biocompatibility and are used in a wide range of biomedical applications, 34,35 highlighted by recent advances in gene delivery vehicles for a variety of therapeutic indications. [36][37][38][39][40][41][42][43] We recently reported a novel class of materials based on cationic poly(a-aminoester) backbones that undergo a pHsensitive rapid and selective degradation to neutral amide and amino acid byproducts in water. 44 We have leveraged this behavior in the design of novel cationic amphiphilic oligomers, charge-altering releasable transporters (CARTs), 33,[45][46][47] that bind, complex, and deliver oligonucleotides of wide ranging size (mRNA, pDNA) into cells, in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and mechanistic investigations of pH-responsive cationic poly(aminoester)s

Blake

Turlington

et al. 2020

Chem. Sci.

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The synthesis and degradation mechanisms of a class of pH-sensitive, rapidly degrading cationic poly(aaminoester)s are described. These reactive, cationic polymers are stable at low pH in water, but undergo a fast and selective degradation at higher pH to liberate neutral diketopiperazines. Related materials incorporating oligo(a-amino ester)s have been shown to be effective gene delivery agents, as the charge-altering degradative behavior facilitates the delivery and release of mRNA and other nucleic acids in vitro and in vivo. Herein, we report detailed studies of the structural and environmental factors that lead to these rapid and selective degradation processes in aqueous buffers. At neutral pH, poly(aaminoester)s derived from N-hydroxyethylglycine degrade selectively by a mechanism involving sequential 1,5-and 1,6-O/N acyl shifts to generate bis(N-hydroxyethyl) diketopiperazine. A family of structurally related cationic poly(aminoester)s was generated to study the structural influences on the degradation mechanism, product distribution, and pH dependence of the rate of degradation. The kinetics and mechanism of the pH-induced degradations were investigated by 1 H NMR, model reactions, and kinetic simulations. These results indicate that polyesters bearing a-ammonium groups and appropriately positioned N-hydroxyethyl substituents are readily cleaved (by intramolecular attack) or hydrolyzed, representing dynamic "dual function" materials that are initially polycationic and transform with changing environment to neutral products. Fig. 1 Proposed mRNA binding and release by Charge-Altering Releasable Transporters (CARTs). Selective degradation of the polycationic poly(a-aminoester) block generates neutral diketopiperazines and hydrolyzed N-hydroxyethyl glycines.Fig. 2 Synthesis of azalactone monomers and polymers.

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“…The development of instructive biomaterials capable of the imparting signals to tissues in which they are in contact with is an inherently interdisciplinary research field, and the subject of increasing attention from researchers in academia and industry. [ 11–13 ] Silk‐based materials with specific chemical, mechanical, and topographical cues have enabled important properties to be engineered into materials for patient‐specific personalized medical devices. [ 14 ] Indeed, it is possible to prepare silk‐based materials with biodegradation rates and mechanical properties controlled by their processing conditions (e.g., choice of solvents, temperatures, etc.…”

Section: Figurementioning

confidence: 99%

Electroactive Silk Fibroin Films for Electrochemically Enhanced Delivery of Drugs

Mousavi

Harper

Municoy

et al. 2020

Macro Materials & Eng

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Biomaterials capable of controlling the delivery of drugs have the potential to treat a variety of conditions. Herein, the preparation of electrically conductive silk fibroin film‐based drug delivery devices is described. Casting aqueous solutions of Bombyx mori silk fibroin, followed by drying and annealing to impart β‐sheets to the silk fibroin, assure that the materials are stable for further processing in water; and the silk fibroin films are rendered conductive by generating an interpenetrating network of a copolymer of pyrrole and 3‐amino‐4‐hydroxybenzenesulfonic acid in the silk fibroin matrix (characterized by a variety of techniques including circular dichroism, Fourier‐transform infrared spectroscopy, nuclear magnetic resonance, Raman spectroscopy, resistance measurements, scanning electron microscopy‐energy dispersive X‐ray spectroscopy, thermogravimetric analysis, X‐ray diffraction, and X‐ray photoelectron spectroscopy). Fibroblasts adhere on the surface of the biomaterials (viability assessed using an (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay and visualized using a confocal microscope), and a fluorescently labeled drug (Texas‐Red Gentamicin) can be loaded electrochemically and released (µg cm−2 quantities) in response to the application of an electrical stimulus.

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Smart Biomaterials: Recent Advances and Future Directions

Cited by 148 publications

References 94 publications

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Synthesis and mechanistic investigations of pH-responsive cationic poly(aminoester)s

Electroactive Silk Fibroin Films for Electrochemically Enhanced Delivery of Drugs

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