Bioinspired nanogels as cell-free DNA trapping and scavenging organelles for rheumatoid arthritis treatment.

Excessive cell-free DNA (cfDNA) in the serum and synovium is considered a causative factor of rheumatoid arthritis (RA). Thus, cfDNA scavenging by using cationic polymers has been an effective therapeutic avenue, while these stratagems still suffer from systemic toxicity and unstable capture of cfDNA. Here, inspired by the biological charge-trapping effects and active degradation function of enzyme-containing organelles in vivo, we proposed a cationic peptide dendrimer nanogel with deoxyribonuclease I (DNase I) conjugation for the treatment of RA. Benefitting from their naturally derived peptide components, the resultant nanogels were highly biocompatible. More attractively, by tailoring them with a larger size and higher surface charge density, these cationic nanogels could achieve the fastest targeting capability, highest accumulation amounts, longer persistence time, and superior DNA scavenging capacity in inflamed joints. Based on these features, we have demonstrated that the organelle mimicking cationic nanogels could significantly down-regulate toll-like receptor (TLR)-9 signaling pathways and attenuate RA symptoms in collagen-induced arthritis mice. These results make the bioinspired DNase I conjugated cationic nanogels an ideal candidate for treating RA and other immune dysregulation diseases.

Engineered mRNA Delivery Systems for Biomedical Applications.

Messenger RNA (mRNA)-based therapeutic strategies have shown remarkable promise in preventing and treating a staggering range of diseases. Optimizing the structure and delivery system of engineered mRNA has greatly improved its stability, immunogenicity, and protein expression levels, which has led to a wider range of uses for mRNA therapeutics. Herein, a thorough analysis of the optimization strategies used in the structure of mRNA is first provided and delivery systems are described in great detail. Furthermore, the latest advancements in biomedical engineering for mRNA technology, including its applications in combatting infectious diseases, treating cancer, providing protein replacement therapy, conducting gene editing, and more, are summarized. Lastly, a perspective on forthcoming challenges and prospects concerning the advancement of mRNA therapeutics is offered. Despite these challenges, mRNA-based therapeutics remain promising, with the potential to revolutionize disease treatment and contribute to significant advancements in the biomedical field.

Breadmaking-Inspired Antioxidant Porous Yeast Microcarriers for Stem Cell Delivery in Diabetic Wound Treatment.

Stem cell-based therapies have exhibited significant promise in the treatment of diabetic ulcers (DU). Nevertheless, enhancing the survival rate and functionality of transplanted stem cells poses a substantial challenge. In this study, inspired by the breadmaking process, yeast microcarriers (YMC) are devised as vehicles for stem cells to address these challenges. The fabrication of YMC involves the amalgamation of microfluidic emulsification with yeast-mediated fermentation, yielding microcarriers with outstanding biocompatibility, high porosity, and antioxidant activity. Adipose-derived stem cells (ADSCs) seeded onto YMC display remarkable cell viability and retain their cellular functions effectively. Additionally, YMC boast a rich glutathione content and exhibit remarkable ROS scavenging ability, thus shielding the ADSCs from oxidative stress. In vivo experiments further substantiate that ADSC@YMC implementation significantly lowered ROS levels in diabetic wounds, resulting in enhanced stem cell retention and improved angiogenesis, collagen deposition, and tissue regeneration. These results highlight the potential of ADSC@YMC as a promising platform for delivering stem cell in the treatment of diabetic wounds.

Viral Mimicking Polyplexes as Hierarchical Unpacking Vectors for Rheumatoid Arthritis Treatment.

Nano-delivery systems hold great promise for the treatment of rheumatoid arthritis (RA). Current research efforts are primarily focused on enhancing their targeting capabilities and efficacy. Here, this study proposes a novel viral-mimicking ternary polyplexes system for the controlled delivery of the anti-inflammatory drug Cyclosporin A (CsA) to effectively treat RA. The ternary polyplexes consist of a nanogel core loaded with CsA and a hyaluronic acid shell, which facilitates CD44-mediated targeting. By mimicking the Trojan Horse strategy employed by viruses, these polyplexes undergo a stepwise process of deshielding and disintegration within the inflamed joints. This process leads to the release of CsA within the cells and the scavenging of pathogenic factors. This study demonstrates that these viral-mimicking ternary polyplexes exhibit rapid targeting, high accumulation, and prolonged persistence in the joints of RA mice. As a result, they effectively reduce inflammation and alleviate symptoms. These results highlight the potential of viral-mimicking ternary polyplexes as a promising therapeutic approach for the targeted and programmed delivery of drugs to treat not only RA but also other autoimmune diseases.

ECM-Inspired Hydrogels with ADSCs Encapsulation for Rheumatoid Arthritis Treatment.

Due to their intrinsic anti-inflammatory and immunomodulatory properties, adipose-derived stem cells (ADSCs) are explored as a promising alternative in treating rheumatoid arthritis (RA). To address the poor survival and function loss of directly injected stem cells, efforts in this area are focus on the generation of efficient cell delivery vehicles. Herein, a novel extracellular matrix (ECM)-inspired injectable hydrogel for ADSCs encapsulation and RA treatment is proposed. The hydrogel with dendritic polylysine and polysaccharide components is formed through the reversible Schiff base crosslinking. It possesses self-healing capability, superior mechanical properties, minimal toxicity, and immunomodulatory ability. When encapsulated with ADSCs, the hydrogel could recover chronic inflammation by directly reversing the dominant macrophage phenotype from M1 to M2 and inhibiting the migration of fibroblast-like synoviocytes. Through a collagen-induced arthritis rat model, the tremendous therapeutic outcomes of this ADSCs-laden hydrogel, including inflammation attenuation, cartilage protection, and bone mineral density promotion are demonstrated. These results make the ECM-inspired hydrogel laden with ADSCs an ideal candidate for treating RA and other autoimmune disorders.

Stem cell niche-inspired microcarriers with ADSCs encapsulation for diabetic wound treatment.

Stem cell therapies have made great progress in the treatment of diabetic wounds during recent decades, while their short in vivo residence, alloimmune reactions, undesired behaviors, and dramatic losses of cell functions still hinder the translation of them into clinic. Here, inspired by the natural components of stem cell niches, we presented novel microfluidic hydrogel microcarriers with extracellular matrix (ECM)-like composition and adipose-derived stem cells (ADSCs) encapsulation for diabetic wound healing. As the hydrogel was synthesized by conjugating hyaluronic acid methacryloyl (HAMA) onto the Fibronectin (FN) molecule chain (FN-HAMA), the laden ADSCs in the microcarriers showed improved bioactivities and pro-regenerative capabilities. Based on these features, we have demonstrated that these ADSCs microcarriers exhibited significant promotion of neovascularization, follicular rejuvenation, and collagen deposition in a mouse diabetic wound model. These results indicated that the stem cell niche-inspired FN-HAMA microcarriers with ADSCs encapsulation have great clinical potential for diabetic wound treatment.

A Dual-Bioinspired Tissue Adhesive Based on Peptide Dendrimer with Fast and Strong Wet Adhesion.

Although tissue adhesives have potential advantages over traditional sutures, existing ones suffer from several limitations: slow adhesion kinetic, low mechanical strength, and poor interfacial bonding with wet biological tissues. Herein, a cooperative mussel/slug double-bioinspired hydrogel adhesive (DBHA) composed of a robust adhesive interface and a stretchable dissipative matrix is developed. The DBHA is formed by a cationic polysaccharide (chitosan), an anionic polysaccharide (carboxymethyl cellulose), and a barbell-like dendritic lysine grafted with catechol groups (G3KPCA). Compared to various commercial bio-glues and traditional adhesives, the DBHA has significantly stronger tissue adhesion and enhanced toughness both ex vivo and in vivo. Meanwhile, the DBHA exhibits fast, strong, tough, and durable adhesion to diverse ex vivo tissue surfaces with blood. The adhesion energy between the adhesive and porcine skin can reach 200-900 J m-2 . Additionally, in vivo studies prove that DBHA has good hemostasis of rabbit artery trauma and achieves better wound healing of tissue incision than commercial bio-glues. This study provides a novel strategy for fabricating fast and strong wet adhesives, which can be used in many applications, such as soft robots, tissue adhesives and hemostats.

A double-network polysaccharide-based composite hydrogel for skin wound healing.

Effective wound dressings are of great significance in preventing infections and promoting wound healing. However, most existing hydrogel dressings have an inadequacy in either mechanical performance, biological activities, or versatilities. Here we presented a double-network cross-linked polysaccharide-based hydrogel composed of collagen peptide-functionalized carboxymethyl chitosan (CS) and oxidized methacrylate sodium alginate (SA). The hydrogel possessed interconnected porous morphologies, suitable swelling ratios, excellent mechanical properties, and favorable biocompatibility. Meanwhile, the in vivo studies using a mouse full-thickness skin defect model showed that the double-network CS/SA hydrogel significantly accelerated wound healing by regulating the inflammatory process, promoting collagen deposition, and improving vascularization. Therefore, the functionalized double-network hydrogel should be a potential candidate as wound dressings.

Injectable Hydrogel Based on Modified Gelatin and Sodium Alginate for Soft-Tissue Adhesive.

To assist or replace the traditional suture techniques for wound closure, soft-tissue adhesives with excellent adhesion strength and favorable biocompatibility are of great significance in biomedical applications. In this study, an injectable hydrogel tissue adhesive containing adipic acid dihydrazide-modified gelatin (Gel-ADH) and oxidized sodium alginate (OSA) was developed. It was found that this tissue adhesive possessed a uniform structure, appropriate swelling ratio, good injectability, and excellent hemocompatibility and cytocompatibility. The adhesion capacity of the developed adhesive with optimized component and concentration was stronger than that of the commercial adhesive Porcine Fibrin Sealant Kit. All these results suggested that the developed hydrogel was a promising candidate for a soft-tissue adhesive.

Fast and High Strength Soft Tissue Bioadhesives Based on a Peptide Dendrimer with Antimicrobial Properties and Hemostatic Ability.

Due to the inconvenience of application, risk of extra damage to fragile soft tissues, and the high incidence of late-stage complications, significant research endeavors have been focused on developing safe and effective bioadhesives to replace or assist the traditional suture techniques for wound closure. Here, we describe a fast and high strength bioadhesive based on polysaccharides and peptide dendrimers (OCMC/G3KP) with inherent hemostatic ability and antibacterial properties. Compared with the commercial bioadhesive Coseal, the OCMC/G3KP hydrogel shows a remarkable 5-fold increase in adhesion strength. The in vivo studies further confirm the superior wound healing performance of the OCMC/G3KP hydrogel in contrast with Coseal and conventional sutures. The OCMC/G3KP hydrogels are efficient and biocompatible bioadhesives with precise controllability that could be flexibly modulated to meet diverse clinical demands.

A facile one-step gelation approach simultaneously combining physical and chemical cross-linking for the preparation of injectable hydrogels.

Injectable hydrogels are promising substrates for tissue engineering and drug delivery applications, while the existing hydrogels and gelation approaches usually have unsatisfactory mechanical strength, notable cytotoxicity, limited controllability, and complex and time-consuming gelation process. Herein, an ultra-facile and versatile approach is reported to overcome these problems via a simultaneously occurring physical (hydrogen bond and π-π stacking) and chemical (transesterification) cross-linking between the polyamidoamine (PAMAM) and N-hydroxysuccinimide/maleimide dual-functionalized PEG (NHS-PEG-MAL). Because of skillfully integrated major advantages of individual physical and chemical cross-linking, as well as due to the simplification of the complex and time-consuming gelation process of sequential multi-step cross-linking, this approach displays various advantages over traditional ones, including excellent mechanical strength, good homogeneity and plasticity, good controllability in gelation rate (tens of seconds to several minutes), porosity and storage modulus (several kPa to several MPa). Moreover, this approach demonstrates a relatively gentle and safe gelation process accompanied by favorable biocompatibility for 3D cell culture. The cell viability of all the resultant hydrogels is >80% after culturing for 2 days, which even increases to >90% for 10% w/v hydrogels. Taken together, this study reports an ultra-facile and versatile approach for the preparation of injectable hydrogels with numerous advanced features enabling various biomedical applications.

Highly Efficient and Safe Delivery of VEGF siRNA by Bioreducible Fluorinated Peptide Dendrimers for Cancer Therapy.

RNA interference (RNAi) has a great promise in treating various acquired and hereditary diseases. However, it remains highly desirable to develop new delivery system to circumvent complex extra- and intracellular barriers for successful clinical translation. Here, we report on a versatile polymeric vector, bioreducible fluorinated peptide dendrimers (BFPD), for efficient and safe small interfering RNA (siRNA) delivery. In virtue of skillfully integrating all of the unique advantages of reversible cross-linking, fluorination, and peptide dendrimers, this novel vector can surmount almost all extra- and intracellular barriers associated with local siRNA delivery through highly improved physiological stability and serum resistance, significantly increased intratumoral enrichment, cellular internalization, successful facilitation of endosomal escape, and cytosolic siRNA release. BFPD polyplexes, carrying small interfering vascular endothelial growth factor (siVEGF), demonstrated excellent VEGF silencing efficacy (∼65%) and a strong capability for inhibiting HeLa cell proliferation. More importantly, these polyplexes showed superior performance in long-term enrichment in the tumor sites and had a high level of tumor growth inhibition. Furthermore, these polyplexes not only exhibited excellent in vivo antitumor efficacy but also demonstrated superior biocompatibility, compared with LPF2000, both in vivo and in vitro. These findings indicate that BFPD is an efficient and safe siRNA delivery system and has remarkable potential for RNAi-based cancer treatment.