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HighlightsPfizer–BioNTech’s and Moderna’s nanotechnology-enabled mRNA vaccines are the first of its kind to be approved for human use.The COVID-19 pandemic has changed our lives and although SARS-CoV-2 has caused irreversible health, social and economic damage, continuous and extensive efforts world-wide were essential to reduce its deleterious effects.During the last decades, the use of nanotechnology in medicine has effectively been translated to the design of drug delivery systems, nanostructured tissues, diagnostic platforms, and novel nanomaterials against several human diseases and infectious pathogens. Nanotechnology-enabled vaccines have been positioned as solutions to mitigate the pandemic outbreak caused by the novel pathogen severe acute respiratory syndrome coronavirus 2. To fast-track the development of vaccines, unprecedented industrial and academic collaborations emerged around the world, resulting in the clinical translation of effective vaccines in less than one year. In this article, we provide an overview of the path to translation from the bench to the clinic of nanotechnology-enabled messenger ribonucleic acid vaccines and examine in detail the types of delivery systems used, their mechanisms of action, obtained results during each phase of their clinical development and their regulatory approval process. We also analyze how nanotechnology is impacting global health and economy during the COVID-19 pandemic and beyond.

HighlightsA novel “nanoengineered hydrogel” barrier based on silicate nanoplatelets and poly(ethylene oxide) (PEO) was developed to prevent the formation of postoperative adhesions.Compared to other hydrogel systems, the prepared biomaterial is injectable and sprayable which makes it compatible with minimally invasive interventions.More than 90% of surgical patients develop postoperative adhesions, and the incidence of hospital re-admissions can be as high as 20%. Current adhesion barriers present limited efficacy due to difficulties in application and incompatibility with minimally invasive interventions. To solve this clinical limitation, we developed an injectable and sprayable shear-thinning hydrogel barrier (STHB) composed of silicate nanoplatelets and poly(ethylene oxide). We optimized this technology to recover mechanical integrity after stress, enabling its delivery though injectable and sprayable methods. We also demonstrated limited cell adhesion and cytotoxicity to STHB compositions in vitro. The STHB was then tested in a rodent model of peritoneal injury to determine its efficacy preventing the formation of postoperative adhesions. After two weeks, the peritoneal adhesion index was used as a scoring method to determine the formation of postoperative adhesions, and STHB formulations presented superior efficacy compared to a commercially available adhesion barrier. Histological and immunohistochemical examination showed reduced adhesion formation and minimal immune infiltration in STHB formulations. Our technology demonstrated increased efficacy, ease of use in complex anatomies, and compatibility with different delivery methods, providing a robust universal platform to prevent postoperative adhesions in a wide range of surgical interventions.

The facile preparation of oxygen-generating microparticles (M) consisting of Polycaprolactone (PCL), Pluronic F-127, and calcium peroxide (CPO) (PCL-F-CPO-M) fabricated through an electrospraying process is disclosed. The biological study confirmed the positive impact from the oxygen-generating microparticles on the cell growth with high viability. The presented technology could work as a prominent tool for various tissue engineering and biomedical applications. The oxygen-generated microparticles fabricated through electrospraying processes were thoroughly characterization through various methods such as X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) analysis, and scanning electron microscopy (SEM)/SEM-Energy Dispersive Spectroscopy (EDS) analysis. The analyses confirmed the presence of the various components and the porous structure of the microparticles. Spherical shape with spongy characteristic microparticles were obtained with negative charge surface (ζ = -16.9) and a size of 17.00 ± 0.34 μm. Furthermore, the biological study performed on rat chondrocytes demonstrated good cell viability and the positive impact of increasing the amount of CPO in the PCL-F-CPO-M. This technological platform could work as an important tool for tissue engineering due to the ability of the microparticles to release oxygen in a sustained manner for up to 7 days with high cell viability.

The engineering of multifunctional surgical bactericidal nanofibers with inherent suitable mechanical and biological properties, through facile and cheap fabrication technology, is a great challenge. Moreover, hernia, which is when organ is pushed through an opening in the muscle or adjacent tissue due to damage of tissue structure or function, is a dire clinical challenge that currently needs surgery for recovery. Nevertheless, post-surgical hernia complications, like infection, fibrosis, tissue adhesions, scaffold rejection, inflammation, and recurrence still remain important clinical problems. Herein, through an integrated electrospinning, plasma treatment and direct surface modification strategy, multifunctional bactericidal nanofibers were engineered showing optimal properties for hernia repair. The nanofibers displayed good bactericidal activity, low inflammatory response, good biodegradation, as well as optimal collagen-, stress fiber- and blood vessel formation and associated tissue ingrowth in vivo. The disclosed engineering strategy serves as a prominent platform for the design of other multifunctional materials for various biomedical challenges.Afewerki et al. employ integrated electrospinning, plasma treatment and direct surface modification strategy to engineer multifunctional bactericidal nanofibers for use in hernia repair. In a mouse model, they demonstrate that these nanofibers display good biological performance with low inflammatory response, good biodegradation and optimal collagen and blood vessel formation and tissue growth.

Constructing in situ tissue engineered heart valves based on xenogeneic decellularized heart valves (DHVs) is a promising strategy for heart valve regeneration. However, the inflammation triggered by foreign body responses results in maladaptive matrix remodeling and compromised mechanical support. Given the critical role of macrophages (Møs) in regulating several homeostasis to relieve xenogeneic rejection and promote tissue regeneration, folic acid modified cerium ions‐tannic acid metal‐polyphenol framework nanoparticles (FCT NPs) have been synthesized via a green coordination method and then loaded onto thiolated DHVs to reprogram macrophage phenotype. FCT NPs, with multiple enzyme‐mimicking activity, biodegradability and biocompatibility, moderately scavenge various reactive oxygen species in M1 Møs, reprogramming them to increase the M2 phenotype. This reduces inflammatory factors levels and promotes secretion of anti‐inflammatory and pro‐regenerative cytokines, enabling elimination of inflammation and promotion of adaptive matrix remodeling. In vitro studies show that FCT‐loaded DHVs (FCT@DHVs) exhibit excellent immunomodulatory capability, mechanical properties, hemocompatibility, and cytocompatibility. Rat implantation models reveal that FCT@DHVs achieve re‐endothelialization and adaptive matrix remodeling via immunomodulation. They also exhibit excellent hemodynamics, hemocompatibility, histocompatibility, anti‐calcification and mechanical support. Notably, M2 Møs numbers decrease with scaffold degradation, indicating self‐adaptive immunomodulation. This strategy offers a promising approach for in situ heart valve regeneration based on xenogeneic DHVs. A novel nanoenzyme based on cerium ions‐tannic acid metal‐polyphenol framework (FCT) has been developed and loaded onto DHVs for targeting M1 macrophages to reduce their ROS level and reprogram macrophage phenotype, thereby eliminating inflammation, promoting endothelialization and adaptive matrix remodeling of scaffolds, offering a promising strategy for constructing TEHV in situ.

In this article number 10.1002/bmm2.70053, Peng Song, Yunlong Wu and their co‐workers developed a novel nanoenzyme based on the folic acid‐modified cerium‐tannic acid metal‐polyphenol framework nanoparticles (FCT NPs). When loaded onto decellularized heart valves (DHVs), the nanoenzyme specifically targeted M1 macrophages, reduced intracellular reactive oxygen species and triggered macrophage phenotypic reprogramming. It further suppressed inflammatory responses, promoted endothelialization and adaptive matrix remodeling of the scaffolds, providing an effective strategy for in situ construction of tissue‐engineered heart valves.

Large-scale vessel-integrated muscle-like lattices (VMLs) containing dense and aligned human induced pluripotent stem cell (hiPSC)-derived myofibers alongside vessel-like microchannels were fabricated using an advanced bioprinting technology and stem cell-laden extracellular matrix-based bioinks.Incorporating vessel-like lattice was of vital importance for enhancing myofiber maturation in vitro and host vessel invasion in vivo, improving implant integration.Successful de novo muscle formation and muscle function restoration was achieved through a combinatorial effect between improved hiPSC-derived VML graft–host integration and increased release of paracrine factors at volumetric muscle loss injury.Observing the human markers in the implantation area confirmed that the hiPSC-muscle precursor cells (MPCs) at the transplantation site play a significant role for improving regenerative capacity of volumetric muscle loss. Engineering biomimetic tissue implants with human induced pluripotent stem cells (hiPSCs) holds promise for repairing volumetric tissue loss. However, these implants face challenges in regenerative capability, survival, and geometric scalability at large-scale injury sites. Here, we present scalable vessel-integrated muscle-like lattices (VMLs), containing dense and aligned hiPSC-derived myofibers alongside passively perfusable vessel-like microchannels inside an endomysium-like supporting matrix using an embedded multimaterial bioprinting technology. The contractile and millimeter-long myofibers are created in mechanically tailored and nanofibrous extracellular matrix-based hydrogels. Incorporating vessel-like lattice enhances myofiber maturation in vitro and guides host vessel invasion in vivo, improving implant integration. Consequently, we demonstrate successful de novo muscle formation and muscle function restoration through a combinatorial effect between improved graft–host integration and its increased release of paracrine factors within volumetric muscle loss injury models. The proposed modular bioprinting technology enables scaling up to centimeter-sized prevascularized hiPSC-derived muscle tissues with custom geometries for next-generation muscle regenerative therapies. [Display omitted] We developed scalable vessel-integrated muscle-like lattices (VMLs) with dense, aligned human induced pluripotent stem cell (hiPSC)-derived myofibers and vessel-like structures using a novel bioprinting technology. These VMLs significantly improved muscle tissue regeneration and function in mice post-volumetric muscle loss. These modular lattices can be adapted to large-scale muscle defects where native regeneration is impaired. To treat volumetric muscle loss in practice, implants should contain enough cell density to compensate for cell death during the implantation procedure and in the early hours of host integration. To this end, we have optimized construct design to achieve highly dense muscle-laden channels with millimeter-long and densely aligned human induced pluripotent stem cell (hiPSC)-derived myofibers. This cell density has proven effective in achieving functional regeneration in the mice tested. However, more studies are needed in larger animals to quantify the number of cells needed for large defects and this study may result in construct pattern redesign. The hiPSC-derived vessel-integrated muscle-like lattices (VMLs) demonstrate successful de novo muscle formation and muscle function restoration through a combinatorial effect between improved graft–host integration and increased release of paracrine factors. As such, we believe that we have achieved a technology readiness level (TRL) 3 in proving that the concept works in vitro and in a relevant environment (e.g., in vivo). Next, the modular building blocks should be assembled and tested in larger defects to validate continuous elastic behavior, large-scale muscle regeneration capacity of the construct, and implant-wide cellular viability. Moreover, the assembly should be implanted in larger animals, for longer durations of culture, to validate long-term muscle functionality to achieve TRL 4. Ultimately, upon successful completion of the mentioned tests, the constructs should be implanted in human defects during clinical trials to inform regeneration efficiency and muscle function restoration.

Heterobifunctional degraders emerge as a novel pharmacologic strategy to treat inflammatory conditions. Previous data have indicated that inflammatory signaling via the myddosome complex is critical for kidney injury and fibrosis development. Within the myddosome, modulation of interleukin-1 receptor associated kinase 4 (IRAK4) by small molecule kinase inhibitors has been shown to reduce fibrosis, but has limited anti-inflammatory effect. Here we used a novel strategy to abrogate IRAK4 by means of targeted ubiquitination triggering proteasomal degradation. We tested the antifibrotic and anti-inflammatory activity of the small molecule IRAK4 degrader KTX-545 in vitro and in vivo in a model of acute kidney injury. Our results indicated that incubation with degrader resulted in abrogation of IRAK4 protein levels, and reduced formation of myddosome complex in primary kidney fibrogenic cells. In human kidney organoids, IRAK4 degradation reduced both extracellular matrix deposition, as well as fibrogenic gene expression caused by tubular damage. Further, the treatment resulted in inhibition of NF-kB activation and downstream inflammatory cytokine expression. In vivo, KTX-545 showed increased efficacy compared to the small molecule IRAK4 kinase inhibitor CA-4948 in ameliorating fibrosis following ischemia/reperfusion injury. Collectively, our results indicate that targeted degradation of IRAK4 is a new promising therapeutic approach for the treatment of renal fibrosing disorders.

The lack of animal models for certain human diseases precludes our understanding of disease mechanisms and our ability to test new therapies in vivo. Here we generated kidney organoids from Tuberous Sclerosis Complex (TSC) patient-derived-hiPSCs to recapitulate a rare kidney tumor called angiomylipoma (AML). Organoids derived from TSC2-/- hiPSCs but not from isogenic TSC2+/- or TSC2+/+ hiPSCs shared a common transcriptional signature and a myomelanocytic cell phenotype with kidney AMLs, and developed epithelial cysts, replicating two major TSC-associated kidney lesions driven by genetic mechanisms that cannot be robustly and consistently recapitulated with transgenic mice. Transplantation of multiple TSC2-/- kidney organoids into the kidneys of immunodeficient rats allowed us to recapitulate AML and cystic kidney disease in vivo, in a scalable fashion and with fidelity, and to test the efficiency of rapamycin-loaded nanoparticles as a novel approach to ablate AMLs by inducing apoptosis triggered by mTOR-inhibition. Collectively, these methods represent a novel tissue-bioengineering strategy for rare disease modeling in vivo. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE171474