Macrophage-modulating nanomedicine for cancer immunotherapy.

Tumor-associated macrophages (TAMs) play crucial roles in the immunosuppressive solid tumor microenvironment (TME). Despite their tumor-promoting functions, TAMs can also be therapeutically modulated to exhibit tumor-killing properties, making them attractive targets for tumor immunotherapy. This review highlights the recent advances in nanomedicine-based strategies centered around macrophages for enhanced cancer immunotherapy. Emerging nanomedicine-based strategies to modulate TAMs in cancer treatment include repolarization of the TAM phenotype, inhibition of monocyte recruitment, depletion of TAMs, and blockage of immune checkpoints. These strategies have shown great promise in significantly improving the efficacy of cancer immunotherapy. Moreover, macrophage-inspired drug delivery systems have demonstrated significant promise in inducing immunotherapeutic effects and enhancing therapeutic efficacy by facilitating evasion from the reticuloendothelial system and promoting accumulation at the tumor site. Finally, we also discuss the challenges and propose future opportunities associated with macrophage-modulating nanomedicine to enhance cancer immunotherapy.

Chemically Modified Platforms for Better RNA Therapeutics.

RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential in disease prevention and treatment. However, despite their remarkable achievements, these therapies encounter substantial challenges including low stability, susceptibility to degradation by nucleases, and a prominent negative charge, thereby hindering further development. Chemically modified platforms have emerged as a strategic innovation, focusing on precise alterations either on the RNA moieties or their associated delivery vectors. This comprehensive review delves into these platforms, underscoring their significance in augmenting the performance and translational prospects of RNA-based therapeutics. It encompasses an in-depth analysis of various chemically modified delivery platforms that have been instrumental in propelling RNA therapeutics toward clinical utility. Moreover, the review scrutinizes the rationale behind diverse chemical modification techniques aiming at optimizing the therapeutic efficacy of RNA molecules, thereby facilitating robust disease management. Recent empirical studies corroborating the efficacy enhancement of RNA therapeutics through chemical modifications are highlighted. Conclusively, we offer profound insights into the transformative impact of chemical modifications on RNA drugs and delineates prospective trajectories for their future development and clinical integration.

Bone Organoids: Recent Advances and Future Challenges.

Bone defects stemming from tumorous growths, traumatic events, and diverse conditions present a profound conundrum in clinical practice and research. While bone has the inherent ability to regenerate, substantial bone anomalies require bone regeneration techniques. Bone organoids represent a new concept in this field, involving the 3D self-assembly of bone-associated stem cells guided in vitro with or without extracellular matrix material, resulting in a tissue that mimics the structural, functional, and genetic properties of native bone tissue. Within the scientific panorama, bone organoids ascend to an esteemed status, securing significant experimental endorsement. Through a synthesis of current literature and pioneering studies, this review offers a comprehensive survey of the bone organoid paradigm, delves into the quintessential architecture and ontogeny of bone, and highlights the latest progress in bone organoid fabrication. Further, existing challenges and prospective directions for future research are identified, advocating for interdisciplinary collaboration to fully harness the potential of this burgeoning domain. Conclusively, as bone organoid technology continues to mature, its implications for both clinical and research landscapes are poised to be profound.

Targeted Protein Fate Modulating Functional Microunits Promotes Intervertebral Fusion.

Stable regulation of protein fate is a prerequisite for successful bone tissue repair. As a ubiquitin-specific protease (USP), USP26 can stabilize the protein fate of ß-catenin to promote the osteogenic activity of mesenchymal cells (BMSCs) and significantly increased bone regeneration in bone defects in aged mice. However, direct transfection of Usp26 in vivo is inefficient. Therefore, improving the efficient expression of USP26 in target cells is the key to promoting bone tissue repair. Herein, 3D printing combined with microfluidic technology is applied to construct a functional microunit (protein fate regulating functional microunit, denoted as PFFM), which includes GelMA microspheres loaded with BMSCs overexpressing Usp26 and seeded into PCL 3D printing scaffolds. The PFFM provides a microenvironment for BMSCs, significantly promotes adhesion, and ensures cell activity and Usp26 supplementation that stabilizes ß-catenin protein significantly facilitates BMSCs to express osteogenic phenotypes. In vivo experiments have shown that PFFM effectively accelerates intervertebral bone fusion. Therefore, PFFM can provide new ideas and alternatives for using USP26 for intervertebral fusion and other hard-to-repair bone defect diseases and is expected to provide clinical translational potential in future treatments.

Intelligent Vascularized 3D/4D/5D/6D-Printed Tissue Scaffolds.

Blood vessels are essential for nutrient and oxygen delivery and waste removal. Scaffold-repairing materials with functional vascular networks are widely used in bone tissue engineering. Additive manufacturing is a manufacturing technology that creates three-dimensional solids by stacking substances layer by layer, mainly including but not limited to 3D printing, but also 4D printing, 5D printing and 6D printing. It can be effectively combined with vascularization to meet the needs of vascularized tissue scaffolds by precisely tuning the mechanical structure and biological properties of smart vascular scaffolds. Herein, the development of neovascularization to vascularization to bone tissue engineering is systematically discussed in terms of the importance of vascularization to the tissue. Additionally, the research progress and future prospects of vascularized 3D printed scaffold materials are highlighted and presented in four categories: functional vascularized 3D printed scaffolds, cell-based vascularized 3D printed scaffolds, vascularized 3D printed scaffolds loaded with specific carriers and bionic vascularized 3D printed scaffolds. Finally, a brief review of vascularized additive manufacturing-tissue scaffolds in related tissues such as the vascular tissue engineering, cardiovascular system, skeletal muscle, soft tissue and a discussion of the challenges and development efforts leading to significant advances in intelligent vascularized tissue regeneration is presented.

Nano-bio interactions in mRNA nanomedicine: Challenges and opportunities for targeted mRNA delivery.

Upon entering the biological milieu, nanomedicines swiftly interact with the surrounding tissue fluid, subsequently being enveloped by a dynamic interplay of biomacromolecules, such as carbohydrates, nucleic acids, and cellular metabolites, but with predominant serum proteins within the biological corona. A notable consequence of the protein corona phenomenon is the unintentional loss of targeting ligands initially designed to direct nanomedicines toward particular cells or organs within the in vivo environment. mRNA nanomedicine displays high demand for specific cell and tissue-targeted delivery to effectively transport mRNA molecules into target cells, where they can exert their therapeutic effects with utmost efficacy. In this review, focusing on the delivery systems and tissue-specific applications, we aim to update the nanomedicine population with the prevailing and still enigmatic paradigm of nano-bio interactions, a formidable hurdle in the pursuit of targeted mRNA delivery. We also elucidate the current impediments faced in mRNA therapeutics and, by contemplating prospective avenues-either to modulate the corona or to adopt an 'ally from adversary' approach-aim to chart a course for advancing mRNA nanomedicine.

Geometric Angles and Gene Expression in Cells for Structural Bone Regeneration.

Geometry and angles play crucial roles in cellular processes; however, its mechanisms of regulation remain unclear. In this study, a series of three dimensional (3D)-printed microfibers with different geometries is constructed using a near-field electrostatic printing technique to investigate the regulatory mechanisms of geometry on stem cell function and bone regeneration. The scaffolds precisely mimicked cell dimensions with high porosity and interoperability. Compared with other spatial topography angles, microfibers with a 90° topology can significantly promote the expression of osteogenic gene proteins in bone marrow-derived mesenchymal stem cells (BMSCs). The effects of different spatial structures on the expression profiles of BMSCs differentiation genes are correlated and validated using microRNA sequencing. Enrichment analysis shows that the 90° microfibers promoted osteogenesis in BMSCs by significantly upregulating miR-222-5p/cbfb/Runx2 expression. The ability of the geometric architecture to promote bone regeneration, as assessed using the cranial defect model, demonstrates that the 90° fiber scaffolds significantly promote new bone regeneration and neovascular neural network formation. This study is the first to elucidate the relationship between angular geometry and cellular gene expression, contributing significantly to the understanding of how geometric architecture can promote stem cell differentiation, proliferation, and function for structural bone regeneration.

Abdominal wall hernia repair: from prosthetic meshes to smart materials.

Hernia reconstruction is one of the most frequently practiced surgical procedures worldwide. Plastic surgery plays a pivotal role in reestablishing desired abdominal wall structure and function without the drawbacks traditionally associated with general surgery as excessive tension, postoperative pain, poor repair outcomes, and frequent recurrence. Surgical meshes have been the preferential choice for abdominal wall hernia repair to achieve the physical integrity and equivalent components of musculofascial layers. Despite the relevant progress in recent years, there are still unsolved challenges in surgical mesh design and complication settlement. This review provides a systemic summary of the hernia surgical mesh development deeply related to abdominal wall hernia pathology and classification. Commercial meshes, the first-generation prosthetic materials, and the most commonly used repair materials in the clinic are described in detail, addressing constrain side effects and rational strategies to establish characteristics of ideal hernia repair meshes. The engineered prosthetics are defined as a transit to the biomimetic smart hernia repair scaffolds with specific advantages and disadvantages, including hydrogel scaffolds, electrospinning membranes, and three-dimensional patches. Lastly, this review critically outlines the future research direction for successful hernia repair solutions by combing state-of-the-art techniques and materials.

Mechanical Signal-Tailored Hydrogel Microspheres Recruit and Train Stem Cells for Precise Differentiation.

The aberrant mechanical microenvironment in degenerated tissues induces misdirection of cell fate, making it challenging to achieve efficient endogenous regeneration. Herein, a hydrogel microsphere-based synthetic niche with integrated cell recruitment and targeted cell differentiation properties via mechanotransduction is constructed . Through the incorporation of microfluidics and photo-polymerization strategies, fibronectin (Fn) modified methacrylated gelatin (GelMA) microspheres are prepared with the independently tunable elastic modulus (1-10Kpa) and ligand density (2 and 10 µg mL-1 ), allowing a wide range of cytoskeleton modulation to trigger the corresponding mechanobiological signaling. The combination of the soft matrix (2Kpa) and low ligand density (2 µg mL-1 ) can support the nucleus pulposus (NP)-like differentiation of intervertebral disc (IVD) progenitor/stem cells by translocating Yes-associated protein (YAP), without the addition of inducible biochemical factors. Meanwhile, platelet-derived growth factor-BB (PDGF-BB) is loaded onto Fn-GelMA microspheres (PDGF@Fn-GelMA) via the heparin-binding domain of Fn to initiate endogenous cell recruitment. In in vivo experiments, hydrogel microsphere-niche maintained the IVD structure and stimulated matrix synthesis. Overall, this synthetic niche with cell recruiting and mechanical training capabilities offered a promising strategy for endogenous tissue regeneration.

Motion lubrication suppressed mechanical activation via hydrated fibrous gene patch for tendon healing.

Mechanical activation of fibroblasts, caused by friction and transforming growth factor-ß1 recognition, is one of the main causes of tissue adhesions. In this study, we developed a lubricated gene-hydrogel patch, which provides both a motion lubrication microenvironment and gene therapy. The patch's outer layer is composed of polyethylene glycol polyester hydrogel. The hydrogel forms hydrogen bonds with water molecules to create the motion lubrication layer, and it also serves as a gene delivery library for long-term gene silencing. Under the motion lubricated microenvironment, extracellular signal-regulated kinase-small interfering RNA can silence fibroblasts and enhance the blocking effect against fibroblast activation. In vitro, the proposed patch effectively inhibits fibroblast activation and reduces the coefficient of friction. In vivo, this patch reduces the expression of vimentin and α-smooth muscle actin in fibroblasts. Therefore, the lubricated gene-hydrogel patch can inhibit the mechanical activation of fibroblasts to promote tendon healing.

A pH-Responsive Cluster Metal-Organic Framework Nanoparticle for Enhanced Tumor Accumulation and Antitumor Effect.

As a result of the deficient tumor-specific antigens, potential off-target effect, and influence of protein corona, metal-organic framework nanoparticles have inadequate accumulation in tumor tissues, limiting their therapeutic effects. In this work, a pH-responsive linker (L) is prepared by covalently modifying oleylamine (OA) with 3-(bromomethyl)-4-methyl-2,5-furandione (MMfu) and poly(ethylene glycol) (PEG). Then, the L is embedded into a solid lipid nanoshell to coat apilimod (Ap)-loaded zeolitic imidazolate framework (Ap-ZIF) to form Ap-ZIF@SLN#L. Under the tumor microenvironment, the hydrophilic PEG and MMfu are removed, exposing the hydrophobic OA on Ap-ZIF@SLN#L, increasing their uptake in cancer cells and accumulation in the tumor. The ZIF@SLN#L nanoparticle induces reactive oxygen species (ROS). Ap released from Ap-ZIF@SLN#L significantly promotes intracellular ROS and lactate dehydrogenase generation. Ap-ZIF@SLN#L inhibits tumor growth, increases the survival rate in mice, activates the tumor microenvironment, and improves the infiltration of macrophages and T cells in the tumor, as demonstrated in two different tumor-bearing mice after injections with Ap-ZIF@SLN#TL. Furthermore, mice show normal tissue structure of the main organs and the normal serum level in alanine aminotransferase and aspartate aminotransferase after treatment with the nanoparticles. Overall, this pH-responsive targeting strategy improves nanoparticle accumulation in tumors with enhanced therapeutic effects.

Inflammation Self-Limiting Electrospun Fibrous Tape via Regional Immunity for Deep Soft Tissue Repair.

Overexpression of inflammatory cytokines and chemokines occurs at deep soft tissue injury sites impeding the inflammation self-limiting and impairing the tissue remodeling process. Inspired by the electrostatically extracellular matrix (ECM) binding property of the inflammatory signals, an inflammation self-limiting fibrous tape is designed by covalently modifying the thermosensitive methacrylated gelatin (GelMA) and negatively charged methacrylated heparin (HepMA) hydrogel mixture with proper ratio onto the electrospun fibrous membrane by mild alkali hydrolysis and carboxyl-amino condensation reaction to restore inflammation self-limiting and promote tissue repair via regional immunity regulation. While the GelMA guarantees cell compatibility, the negatively charged HepMA successfully adsorbs the inflammatory cytokines and chemokines by electrostatic interactions and inhibits immune cell migration in vitro. Furthermore, in vivo inflammation self-limiting and regional immunity regulation efficacy is evaluated in a rat abdominal hernia model. Reduced local inflammatory cytokines and chemokines in the early stage and increased angiogenesis and ECM remodeling in the later phase confirm that the tape is an approach to maintain an optimal regional immune activation level after soft tissue injury. Overall, the reported electrospun fibrous tape will find its way into clinical transformation and solve the challenges of deep soft tissue injury.

Local bone metabolism balance regulation via double-adhesive hydrogel for fixing orthopedic implants.

The effective osteointegration of orthopedic implants is a key factor for the success of orthopedic surgery. However, local metabolic imbalance around implants under osteoporosis condition could jeopardize the fixation effect. Inspired by the bone structure and the composition around implants under osteoporosis condition, alendronate (A) was grafted onto methacryloyl hyaluronic acid (H) by activating the carboxyl group of methacryloyl hyaluronic acid to be bonded to inorganic calcium phosphate on trabecular bone, which is then integrated with aminated bioactive glass (AB) modified by oxidized dextran (O) for further adhesion to organic collagen on the trabecular bone. The hybrid hydrogel could be solidified on cancellous bone in situ under UV irradiation and exhibits dual adhesion to organic collagen and inorganic apatite, promoting osteointegration of orthopedic implants, resulting in firm stabilization of the implants in cancellous bone areas. In vitro, the hydrogel was evidenced to promote osteogenic differentiation of embryonic mouse osteoblast precursor cells (MC3T3-E1) as well as inhibit the receptor activator of nuclear factor-κ B ligand (RANKL)-induced osteoclast differentiation of macrophages, leading to the upregulation of osteogenic-related gene and protein expression. In a rat osteoporosis model, the bone-implant contact (BIC) of the hybrid hydrogel group increased by 2.77, which is directly linked to improved mechanical stability of the orthopedic implants. Overall, this organic-inorganic, dual-adhesive hydrogel could be a promising candidate for enhancing the stability of orthopedic implants under osteoporotic conditions.

Regulated Exogenous/Endogenous Inflammation via "Inner-Outer" Medicated Electrospun Fibers for Promoting Tissue Reconstruction.

Regenerative medicine aims to provide solutions for structural and functional recovery in conditions where organs suffer from varying degrees of diseases or injuries. However, the exogenous inflammation triggered by implanted biomaterials and endogenous inflammation caused by some disease or tissue destruction has not been solved properly yet. Herein, a functional "inner-outer" medicated core-shell electrospun fibrous membrane is fabricated with RGD surface modification for exogenous inflammation suppression and puerarin loading in the core for long-term endogenous inflammation inhibition through microsol electrospinning technique. The "outer" RGD significantly increases biocompatibility of fibrous membrane through promoting cell viability, adhesion, and proliferation while the "inner" puerarin suppresses inflammatory gene expression via sustained drug release in vitro. Moreover, in a rat abdominal wall hernia model, the functional fibrous membrane successfully reduces exogenous and endogenous inflammation response and promotes wound healing through collagen deposition, smooth muscle formation, and vascularization. In summary, the functional "inner-outer" medicated fibrous membrane holds a great potential for clinical treatment of diseases that needs tissue reconstruction structurally and functionally accompanied by immunoregulation.

Capturing dynamic biological signals via bio-mimicking hydrogel for precise remodeling of soft tissue.

Soft tissue remodeling is a sophisticated process that sequentially provides dynamic biological signals to guide cell behavior. However, capturing these signals within hydrogel and directing over time has still been unrealized owing to the poor comprehension of physiological processes. Here, a bio-mimicking hydrogel is designed via thiol-ene click reaction to capture the early physical signal triggered by inflammation, and the chemical signals provided with chemokine and natural adhesion sites, which guaranteed the precise soft tissue remodeling. This bio-mimicking hydrogel efficiently facilitated cell anchoring, migration, and invasion in the 3D matrix due to the permissive space and the interaction with integrin receptors. Besides, the covalently grafted chemokine-like peptide is optimal for colonization and functional differentiation of endothelial cells through a HIF-1α dependent signal pathway. Furthermore, the early polarization of macrophages, collagen deposition and angiogenesis in rat acute wound model, and the increased blood perfusion in mouse skin flap model have confirmed that the bio-mimicking hydrogel realized precise soft tissue remodeling and opens new avenues for the phased repair of different tissues such as nerve, myocardium, and even bone.

Microenvironment-Protected Exosome-Hydrogel for Facilitating Endometrial Regeneration, Fertility Restoration, and Live Birth of Offspring.

Thin endometrium is a primary cause of failed embryo transfer, resulting in long-term infertility and negative family outcomes. While hormonal treatments have greatly improved fertility results for some women, these responses remain unsatisfactory due to damage and infection of the complex endometrial microenvironment. In this study, a multifunctional microenvironment-protected exosome-hydrogel is designed for facilitating endometrial regeneration and fertility restoration via in situ microinjection and endometrial regeneration. This exosome hydrogel is formulated via Ag+ -S dynamic coordination and fusion with adipose stem cell-derived exosomes (ADSC-exo), yielding an injectable preparation that is sufficient to mitigate infection risk while also possessing the antigenic contents and paracrine signaling activity of the ADSC source cells, enabling regeneration of the endometrial microenvironment. In vitro, this exosome-hydrogel exerts an outstanding neovascularization-promoting effect, increased human umbilical vein endothelial cell proliferation and tube formation for 1.87 and 2.2 folds. In vivo, microenvironment-protected exosome-hydrogel also reveals to promote neovascularization and tissue regeneration while suppressing local tissue fibrosis. Importantly, regenerated endometrial tissue is more receptive to give embryos and birth to a healthy newborn. This microenvironment-protected exosome-hydrogel system offers a convenient, safe, and noninvasive approach for repairing thin endometrium and fertility restoration.

Lotus seedpod-inspired internal vascularized 3D printed scaffold for bone tissue repair.

In the field of bone defect repair, 3D printed scaffolds have the characteristics of personalized customization and accurate internal structure. However, how to construct a well-structured vascular network quickly and effectively inside the scaffold is essential for bone repair after transplantation. Herein, inspired by the unique biological structure of "lotus seedpod", hydrogel microspheres encapsulating deferoxamine (DFO) liposomes were prepared through microfluidic technology as "lotus seeds", and skillfully combined with a three-dimensional (3D) printed bioceramic scaffold with biomimetic "lotus" biological structure which can internally grow blood vessels. In this composite scaffold system, DFO was effectively released by 36% in the first 6 h, which was conducive to promote the growth of blood vessels inside the scaffold quickly. In the following 7 days, the release rate of DFO reached 69%, which was fundamental in the formation of blood vessels inside the scaffold as well as osteogenic differentiation of bone mesenchymal stem cells (BMSCs). It was confirmed that the composite scaffold could significantly promote the human umbilical vein endothelial cells (HUVECs) to form the vascular morphology within 6 h in vitro. In vivo, the composite scaffold increased the expression of vascularization and osteogenic related proteins Hif1-α, CD31, OPN, and OCN in the rat femoral defect model, significantly cutting down the time of bone repair. To sum up, this "lotus seedpod" inspired porous bioceramic 3D printed scaffold with internal vascularization functionality has broad application prospects in the future.