Photonic control of ligand nanospacing in self-assembly regulates stem cell fate.

Extracellular matrix (ECM) undergoes dynamic inflation that dynamically changes ligand nanospacing but has not been explored. Here we utilize ECM-mimicking photocontrolled supramolecular ligand-tunable Azo+ self-assembly composed of azobenzene derivatives (Azo+) stacked via cation-π interactions and stabilized with RGD ligand-bearing poly(acrylic acid). Near-infrared-upconverted-ultraviolet light induces cis-Azo+-mediated inflation that suppresses cation-π interactions, thereby inflating liganded self-assembly. This inflation increases nanospacing of "closely nanospaced" ligands from 1.8 nm to 2.6 nm and the surface area of liganded self-assembly that facilitate stem cell adhesion, mechanosensing, and differentiation both in vitro and in vivo, including the release of loaded molecules by destabilizing water bridges and hydrogen bonds between the Azo+ molecules and loaded molecules. Conversely, visible light induces trans-Azo+ formation that facilitates cation-π interactions, thereby deflating self-assembly with "closely nanospaced" ligands that inhibits stem cell adhesion, mechanosensing, and differentiation. In stark contrast, when ligand nanospacing increases from 8.7 nm to 12.2 nm via the inflation of self-assembly, the surface area of "distantly nanospaced" ligands increases, thereby suppressing stem cell adhesion, mechanosensing, and differentiation. Long-term in vivo stability of self-assembly via real-time tracking and upconversion are verified. This tuning of ligand nanospacing can unravel dynamic ligand-cell interactions for stem cell-regulated tissue regeneration.

Effective Modulation of Inflammation and Oxidative Stress for Enhanced Regeneration of Intervertebral Discs Using 3D Porous Hybrid Protein Nanoscaffold.

Degeneration of fibrocartilaginous tissues is often associated with complex pro-inflammatory factors. These include reactive oxygen species (ROS), cell-free nucleic acids (cf-NAs), and epigenetic changes in immune cells. To effectively control this complex inflammatory signaling, it developed an all-in-one nanoscaffold-based 3D porous hybrid protein (3D-PHP) self-therapeutic strategy for treating intervertebral disc (IVD) degeneration. The 3D-PHP nanoscaffold is synthesized by introducing a novel nanomaterial-templated protein assembly (NTPA) strategy. 3D-PHP nanoscaffolds that avoid covalent modification of proteins demonstrate inflammatory stimuli-responsive drug release, disc-mimetic stiffness, and excellent biodegradability. Enzyme-like 2D nanosheets incorporated into nanoscaffolds further enabled robust scavenging of ROS and cf-NAs, reducing inflammation and enhancing the survival of disc cells under inflammatory stress in vitro. Implantation of 3D-PHP nanoscaffolds loaded with bromodomain extraterminal inhibitor (BETi) into a rat nucleotomy disc injury model effectively suppressed inflammation in vivo, thus promoting restoration of the extracellular matrix (ECM). The resulting regeneration of disc tissue facilitated long-term pain reduction. Therefore, self-therapeutic and epigenetic modulator-encapsulated hybrid protein nanoscaffold shows great promise as a novel approach to restore dysregulated inflammatory signaling and treat degenerative fibrocartilaginous diseases, including disc injuries, providing hope and relief to patients worldwide.

Development of a Nanohybrid Peptide Hydrogel for Enhanced Intervertebral Disc Repair and Regeneration.

Effective therapeutic approaches to overcome the heterogeneous pro-inflammatory and inhibitory extracellular matrix (ECM) microenvironment are urgently needed to achieve robust structural and functional repair of severely wounded fibrocartilaginous tissues. Herein we developed a dynamic and multifunctional nanohybrid peptide hydrogel (NHPH) through hierarchical self-assembly of peptide amphiphile modified with biodegradable two-dimensional nanomaterials with enzyme-like functions. NHPH is not only injectable, biocompatible, and biodegradable but also therapeutic by catalyzing the scavenging of pro-inflammatory reactive oxygen species and promoting ECM remodeling. In addition, our NHPH method facilitated the structural and functional recovery of the intervertebral disc (IVD) after severe injuries by delivering pro-regenerative cytokines in a sustained manner, effectively suppressing immune responses and eventually restoring the regenerative microenvironment of the ECM. In parallel, the NHPH-enhanced nucleus pulposus cell differentiation and pain reduction in a rat nucleotomy model further validated the therapeutic potential of NHPH. Collectively, our advanced nanoscaffold technology will provide an alternative approach for the effective treatment of IVD degeneration as well as other fibrocartilaginous tissue injuries.

Nanoparticle-Based Artificial Mitochondrial DNA Transcription Regulator: MitoScript.

The growing knowledge of the links between aberrant mitochondrial gene transcription and human diseases necessitates both an effective and dynamic approach to control mitochondrial DNA (mtDNA) transcription. To address this challenge, we developed a nanoparticle-based synthetic mitochondrial transcription regulator (MitoScript). MitoScript provides great colloidal stability, excellent biocompatibility, efficient cell uptake, and selective mitochondria targeting and can be monitored in live cells using near-infrared fluorescence. Notably, MitoScript controlled mtDNA transcription in a human cell line in an effective and selective manner. MitoScript targeting the light strand promoter region of mtDNA resulted in the downregulation of ND6 gene silencing, which eventually affected cell redox status, with considerably increased reactive oxygen species (ROS) generation. In summary, we developed MitoScript for the efficient, nonviral modification of mitochondrial DNA transcription. Our platform technology can potentially contribute to understanding the fundamental mechanisms of mitochondrial disorders and developing effective treatments for mitochondrial diseases.

Injectable bioorthogonal hydrogel (BIOGEL) accelerates tissue regeneration in degenerated intervertebral discs.

Intervertebral disc (IVD) degeneration is a leading cause of back pain and precursor to more severe conditions, including disc herniation and spinal stenosis. While traditional growth factor therapies (e.g., TGFß) are effective at transiently reversing degenerated disc by stimulation of matrix synthesis, it is increasingly accepted that bioscaffolds are required for sustained, complete IVD regeneration. Current scaffolds (e.g., metal/polymer composites, non-mammalian biopolymers) can be improved in one or more IVD regeneration demands: biodegradability, noninvasive injection, recapitulated healthy IVD biomechanics, predictable crosslinking, and matrix repair induction. To meet these demands, tetrazine-norbornene bioorthogonal ligation was combined with gelatin to create an injectable bioorthogonal hydrogel (BIOGEL). The liquid hydrogel precursors remain free-flowing across a wide range of temperatures and crosslink into a robust hydrogel after 5-10 min, allowing a human operator to easily inject the therapeutic constructs into degenerated IVD. Moreover, BIOGEL encapsulation of TGFß potentiated histological repair (e.g., tissue architecture and matrix synthesis) and functional recovery (e.g., high water retention by promoting the matrix synthesis and reduced pain) in an in vivo rat IVD degeneration/nucleotomy model. This BIOGEL procedure readily integrates into existing nucleotomy procedures, indicating that clinical adoption should proceed with minimal difficulty. Since bioorthogonal crosslinking is essentially non-reactive towards biomolecules, our developed material platform can be extended to other payloads and degenerative injuries.

Structurally Defined Water-Soluble Metallofullerene Derivatives towards Biomedical Applications.

Endohedral metallofullerenes (EMFs) are excellent carriers of rare-earth element (REE) ions in biomedical applications because they preclude the release of toxic metal ions. However, existing approaches to synthesize water-soluble EMF derivatives yield mixtures that inhibit precise drug design. Here we report the synthesis of metallobuckytrio (MBT), a three-buckyball system, as a modular platform to develop structurally defined water-soluble EMF derivatives with ligands by choice. Demonstrated with PEG ligands, the resulting water-soluble MBTs show superb biocompatibility. The Gd MBTs exhibit superior T1 relaxivity than typical Gd complexes, potentially superseding current clinical MRI contrast agents in both safety and efficiency. The Lu MBTs generated reactive oxygen species upon light irradiation, showing promise as photosensitizers. With their modular nature to incorporate other ligands, we anticipate the MBT platform to open new paths towards bio-specific REE drugs.

High-Content Screening and Analysis of Stem Cell-Derived Neural Interfaces Using a Combinatorial Nanotechnology and Machine Learning Approach.

A systematic investigation of stem cell-derived neural interfaces can facilitate the discovery of the molecular mechanisms behind cell behavior in neurological disorders and accelerate the development of stem cell-based therapies. Nevertheless, high-throughput investigation of the cell-type-specific biophysical cues associated with stem cell-derived neural interfaces continues to be a significant obstacle to overcome. To this end, we developed a combinatorial nanoarray-based method for high-throughput investigation of neural interface micro-/nanostructures (physical cues comprising geometrical, topographical, and mechanical aspects) and the effects of these complex physical cues on stem cell fate decisions. Furthermore, by applying a machine learning (ML)-based analytical approach to a large number of stem cell-derived neural interfaces, we comprehensively mapped stem cell adhesion, differentiation, and proliferation, which allowed for the cell-type-specific design of biomaterials for neural interfacing, including both adult and human-induced pluripotent stem cells (hiPSCs) with varying genetic backgrounds. In short, we successfully demonstrated how an innovative combinatorial nanoarray and ML-based platform technology can aid with the rational design of stem cell-derived neural interfaces, potentially facilitating precision, and personalized tissue engineering applications.

Photoswitchable Microgels for Dynamic Macrophage Modulation.

Dynamic manipulation of supramolecular self-assembled structures is achieved irreversibly or under non-physiological conditions, thereby limiting their biomedical, environmental, and catalysis applicability. In this study, microgels composed of azobenzene derivatives stacked via π-cation and π-π interactions are developed that are electrostatically stabilized with Arg-Gly-Asp (RGD)-bearing anionic polymers. Lateral swelling of RGD-bearing microgels occurs via cis-azobenzene formation mediated by near-infrared-light-upconverted ultraviolet light, which disrupts intermolecular interactions on the visible-light-absorbing upconversion-nanoparticle-coated materials. Real-time imaging and molecular dynamics simulations demonstrate the deswelling of RGD-bearing microgels via visible-light-mediated trans-azobenzene formation. Near-infrared light can induce in situ swelling of RGD-bearing microgels to increase RGD availability and trigger release of loaded interleukin-4, which facilitates the adhesion structure assembly linked with pro-regenerative polarization of host macrophages. In contrast, visible light can induce deswelling of RGD-bearing microgels to decrease RGD availability that suppresses macrophage adhesion that yields pro-inflammatory polarization. These microgels exhibit high stability and non-toxicity. Versatile use of ligands and protein delivery can offer cytocompatible and photoswitchable manipulability of diverse host cells.

Material Engineering in Gut Microbiome and Human Health.

Tremendous progress has been made in the past decade regarding our understanding of the gut microbiome's role in human health. Currently, however, a comprehensive and focused review marrying the two distinct fields of gut microbiome and material research is lacking. To bridge the gap, the current paper discusses critical aspects of the rapidly emerging research topic of "material engineering in the gut microbiome and human health." By engaging scientists with diverse backgrounds in biomaterials, gut-microbiome axis, neuroscience, synthetic biology, tissue engineering, and biosensing in a dialogue, our goal is to accelerate the development of research tools for gut microbiome research and the development of therapeutics that target the gut microbiome. For this purpose, state-of-the-art knowledge is presented here on biomaterial technologies that facilitate the study, analysis, and manipulation of the gut microbiome, including intestinal organoids, gut-on-chip models, hydrogels for spatial mapping of gut microbiome compositions, microbiome biosensors, and oral bacteria delivery systems. In addition, a discussion is provided regarding the microbiome-gut-brain axis and the critical roles that biomaterials can play to investigate and regulate the axis. Lastly, perspectives are provided regarding future directions on how to develop and use novel biomaterials in gut microbiome research, as well as essential regulatory rules in clinical translation. In this way, we hope to inspire research into future biomaterial technologies to advance gut microbiome research and gut microbiome-based theragnostics.

Excellent Energy Storage Properties Achieved in Sodium Niobate-Based Relaxor Ceramics through Doping Tantalum.

Lead-free relaxor ferroelectric ceramics are potential for energy storage applications due to their comprehensive energy storage properties. However, the energy efficiency of many relaxor ceramics is not high enough, leading to high Joule heat during the charge-discharge cycles, thus lowering their energy storage performance. In this work, tantalum (Ta) dopants were introduced into sodium niobate-based relaxor ceramics to improve the resistivity and energy efficiency. The leakage current was reduced by Ta doping, especially at the high electric field. The enhanced resistivity is attributed to the increased bandgap induced by Ta doping. The impedance spectroscopy shows that both the grain and grain boundary resistivities are improved in the high temperature region. As a result, the optimal recoverable energy density and energy efficiency are 6.5 J/cm3 and 94% at 450 kV/cm, respectively. In addition, the energy storage properties exhibit satisfactory temperature stability and cycling reliability. All these merits demonstrate that the Ta modified sodium niobate-based relaxor ceramic a potential candidate for high-power energy storage applications.

Advanced Drug Delivery Modulation via Hybrid Nanofibers Enhances Stem Cell Differentiation.

Seamlessly integrating soluble factors onto biomedical scaffolds with a precisely manufactured topography for efficient cell control remains elusive since many scaffold fabrication techniques degrade payloads. Surface adsorption of payloads onto synthesized nanoscaffolds retains bioactivity by removing exposure to harsh processing conditions at the expense of inefficient drug loading and uncontrolled release. Herein, we present a nanomaterial composite scaffold paradigm to improve physicochemical surface adsorption pharmacokinetics. As a proof of concept, we integrated graphene oxide (GO) and manganese dioxide (MnO2) nanosheets onto nanofibers to increase loading capacity and tune drug release. Non-degradable GO enhances payload retention, while biodegradable MnO2 enables cell-responsive drug release. To demonstrate the utility of this hybrid nanomaterial scaffold paradigm for tissue engineering, we adsorbed payloads ranging from small molecules to proteins onto the scaffold to induce myogenesis and osteogenesis for multiple stem cell lines. Scaffolds with adsorbed payloads enabled more efficient differentiation than media supplementation using equivalent quantities of differentiation factors. We attribute this increased efficacy to a reverse uptake mechanism whereby payloads are localized around seeded cells, increasing delivery efficiency for guiding differentiation. Additionally, we demonstrate spatial control over cells since differentiation factors are delivered locally through the scaffold. When co-culturing scaffolds with and without adsorbed payloads, only cells seeded on payload-adsorbed scaffolds underwent differentiation. With this modular technology being capable of enhancing multiple differentiation fates for specific cell lines, this technology provides a promising alternative for current tissue engineering scaffolds.

Injectable hybrid inorganic nanoscaffold as rapid stem cell assembly template for cartilage repair.

Cartilage injuries are often devastating and most cannot be cured because of the intrinsically low regenerative capacity of cartilage tissues. Although stem-cell therapy has shown enormous potential for cartilage repair, the therapeutic outcome has been restricted by low survival rates and poor chondrocyte differentiation in vivo. Here, we report an injectable hybrid inorganic (IHI) nanoscaffold that facilitates fast assembly, enhances survival and regulates chondrogenic differentiation of stem cells. IHI nanoscaffolds that strongly bind to extracellular matrix (ECM) proteins assemble stem cells through synergistic 3D cell-cell and cell-matrix interactions, creating a favorable physical microenvironment for stem-cell survival and differentiation in vitro and in vivo. Additionally, chondrogenic factors can be loaded into nanoscaffolds with a high capacity, which allows deep, homogenous drug delivery into assembled 3D stem-cell-derived tissues for effective control over the soluble microenvironment of stem cells. The developed IHI nanoscaffolds that assemble with stem cells are injectable. They also scavenge reactive oxygen species and timely biodegrade for proper integration into injured cartilage tissues. Implantation of stem-cell-assembled IHI nanoscaffolds into injured cartilage results in accelerated tissue regeneration and functional recovery. By establishing our IHI nanoscaffold-templated 3D stem-cell assembly method, we provide a promising approach to better overcoming the inhibitory microenvironment associated with cartilage injuries and to advance current stem-cell-based tissue engineering.

Submolecular Ligand Size and Spacing for Cell Adhesion.

Cell adhesion occurs when integrin recognizes and binds to Arg-Gly-Asp (RGD) ligands present in fibronectin. In this work, submolecular ligand size and spacing are tuned via template-mediated in situ growth of nanoparticles for dynamic macrophage modulation. To tune liganded gold nanoparticle (GNP) size and spacing from 3 to 20 nm, in situ localized assemblies of GNP arrays on nanomagnetite templates are engineered. 3 nm-spaced ligands stimulate the binding of integrin, which mediates macrophage-adhesion-assisted pro-regenerative polarization as compared to 20 nm-spaced ligands, which can be dynamically anchored to the substrate for stabilizing integrin binding and facilitating dynamic macrophage adhesion. Increasing the ligand size from 7 to 20 nm only slightly promotes macrophage adhesion, not observed with 13 nm-sized ligands. Increasing the ligand spacing from 3 to 17 nm significantly hinders macrophage adhesion that induces inflammatory polarization. Submolecular tuning of ligand spacing can dominantly modulate host macrophages.

Predictive Biophysical Cue Mapping for Direct Cell Reprogramming Using Combinatorial Nanoarrays.

Biophysical cues, such as nanotopographies of extracellular matrix (ECM), are key cell regulators for direct cell reprogramming. Therefore, high-throughput methods capable of systematically screening a wide range of biophysical cue-regulated cell reprogramming are increasingly needed for tissue engineering and regenerative medicine. Here, we report the development of a dynamic laser interference lithography (DIL) to generate large-scale combinatorial biophysical cue (CBC) arrays with diverse micro/nanostructures at higher complexities than most current arrays. Using CBC arrays, a high-throughput cell mapping method is further demonstrated for the systematic investigation of biophysical cue-mediated direct cell reprogramming. This CBC array-based high-throughput cell screening approach facilitates the rapid identification of unconventional hierarchical nanopatterns that induce the direct reprogramming of human fibroblasts into neurons through epigenetic modulation mechanisms. In this way, we successfully demonstrate DIL for generating highly complex CBC arrays and establish CBC array-based cell screening as a valuable strategy for systematically investigating the role of biophysical cues in cell reprogramming.

Harnessing the Therapeutic Potential of Extracellular Vesicles for Biomedical Applications Using Multifunctional Magnetic Nanomaterials.

Extracellular vesicles (e.g., exosomes) carrying various biomolecules (e.g., proteins, lipids, and nucleic acids) have rapidly emerged as promising platforms for many biomedical applications. Despite their enormous potential, their heterogeneity in surfaces and sizes, the high complexity of cargo biomolecules, and the inefficient uptake by recipient cells remain critical barriers for their theranostic applications. To address these critical issues, multifunctional nanomaterials, such as magnetic nanomaterials, with their tunable physical, chemical, and biological properties, may play crucial roles in next-generation extracellular vesicles (EV)-based disease diagnosis, drug delivery, tissue engineering, and regenerative medicine. As such, one aims to provide cutting-edge knowledge pertaining to magnetic nanomaterials-facilitated isolation, detection, and delivery of extracellular vesicles and their associated biomolecules. By engaging the fields of extracellular vesicles and magnetic nanomaterials, it is envisioned that their properties can be effectively combined for optimal outcomes in biomedical applications.

Hybrid SMART spheroids to enhance stem cell therapy for CNS injuries.

Although stem cell therapy holds enormous potential for treating debilitating injuries and diseases in the central nervous system, low survival and inefficient differentiation have restricted its clinical applications. Recently, 3D cell culture methods, such as stem cell­based spheroids and organoids, have demonstrated advantages by incorporating tissue-mimetic 3D cell-cell interactions. However, a lack of drug and nutrient diffusion, insufficient cell-matrix interactions, and tedious fabrication procedures have compromised their therapeutic effects in vivo. To address these issues, we developed a biodegradable nanomaterial-templated 3D cell assembly method that enables the formation of hybrid stem cell spheroids with deep drug delivery capabilities and homogeneous incorporation of 3D cell-matrix interactions. Hence, high survival rates, controlled differentiation, and functional recovery were demonstrated in a spinal cord injury animal model. Overall, our hybrid stem cell spheroids represent a substantial development of material-facilitated 3D cell culture systems and can pave the way for stem cell­based treatment of CNS injuries.

Clustered Regularly Interspaced Short Palindromic Repeats-Mediated Amplification-Free Detection of Viral DNAs Using Surface-Enhanced Raman Spectroscopy-Active Nanoarray.

Nucleic acid biomarkers have been widely used to detect various viral-associated diseases, including the recent pandemic COVID-19. The CRISPR-Cas-based trans-activating phenomenon has shown excellent potential for developing sensitive and selective detection of nucleic acids. However, the nucleic acid amplification steps are typically required when sensitive and selective monitoring of the target nucleic acid is needed. To overcome the aforementioned challenges, we developed a CRISPR-Cas12a-based nucleic acid amplification-free biosensor by a surface-enhanced Raman spectroscopy (SERS)-assisted ultrasensitive detection system. We integrated the activated CRISPR-Cas12a by viral DNA with a Raman-sensitive system composed of ssDNA-immobilized Raman probe-functionalized Au nanoparticles (RAuNPs) on the graphene oxide (GO)/triangle Au nanoflower array. Using this CRISPR-based Raman-sensitive system improved the detection sensitivity of the multiviral DNAs such as hepatitis B virus (HBV), human papillomavirus 16 (HPV-16), and HPV-18 with an extremely low detection limit and vast detection range from 1 aM to 100 pM without the amplification steps. We suggest that this ultrasensitive amplification-free detection system for nucleic acids can be widely applied to the precise and early diagnosis of viral infections, cancers, and several genetic diseases.

Hybrid Graphene-Gold Nanoparticle-based Nucleic Acid Conjugates for Cancer-Specific Multimodal Imaging and Combined Therapeutics.

Nanoparticle-based nucleic acid conjugates (NP-NACs) hold great promise for theragnostic (diagnostic and therapeutic) applications. However, several limitations have hindered the realization of their full potential in the clinical treatment of cancer and other diseases. In diagnosis, NP-NACs, combined with conventional optical sensing systems, have been applied for cancer detection in vitro, but low signal-to-noise ratios limit their broad in vivo applications. Meanwhile, the efficiency of NP-NAC-mediated cancer therapies has been limited through the adaptation of alternative pro-survival pathways in cancer cells. The recent emergence of personalized and precision medicine has outlined the importance of both accurate diagnosis and efficient therapeutics in a single platform. As such, we report the controlled assembly of hybrid graphene oxide/gold nanoparticle-based cancer-specific NACs (Au@GO NP-NACs) for multimodal imaging and combined therapeutics. Our developed Au@GO NP-NACs shows excellent surface-enhanced Raman scattering (SERS)-mediated live-cell cancer detection and multimodal synergistic cancer therapy through the use of photothermal, genetic, and chemotherapeutic strategies. Synergistic and selective killing of cancer cells were then demonstrated by using in vitro microfluidic models and nine different cancer cell lines by further incorporating near-infrared photothermal hyperthermia, a Topoisomerase II anti-cancer drug, and cancer targeting peptides. Moreover, with distinctive advantages of the Au@GO NP-NACs for cancer theragnostics, we further demonstrated precision cancer treatment through the detection of cancer cells in vivo using SERS followed by efficient ablation of the tumor. Therefore, our Au@GO NP-NACs could pave a new road for the advanced theragnostics of cancer as well as many other diseases.

In Situ Detection of Neurotransmitters from Stem Cell-Derived Neural Interface at the Single-Cell Level via Graphene-Hybrid SERS Nanobiosensing.

In situ quantitative measurements of neurotransmitter activities can provide useful insights into the underlying mechanisms of stem cell differentiation, the formation of neuronal networks, and neurodegenerative diseases. Currently, neurotransmitter detection methods suffer from poor spatial resolution, nonspecific detection, and a lack of in situ analysis. To address this challenge, herein, we first developed a graphene oxide (GO)-hybrid nanosurface-enhanced Raman scattering (SERS) array to detect dopamine (DA) in a selective and sensitive manner. Using the GO-hybrid nano-SERS array, we successfully measured a wide range of DA concentrations (10-4 to 10-9 M) rapidly and reliably. Moreover, the measurement of DA from differentiating neural stem cells applies to the characterization of neuronal differentiation. Given the challenges of in situ detection of neurotransmitters at the single-cell level, our developed SERS-based detection method can represent a unique tool for investigating single-cell signaling pathways associated with DA, or other neurotransmitters, and their roles in neurological processes.

Effective Modulation of CNS Inhibitory Microenvironment using Bioinspired Hybrid-Nanoscaffold-Based Therapeutic Interventions.

Central nervous system (CNS) injuries are often debilitating, and most currently have no cure. This is due to the formation of a neuroinhibitory microenvironment at injury sites, which includes neuroinflammatory signaling and non-permissive extracellular matrix (ECM) components. To address this challenge, a viscous interfacial self-assembly approach, to generate a bioinspired hybrid 3D porous nanoscaffold platform for delivering anti-inflammatory molecules and establish a favorable 3D-ECM environment for the effective suppression of the neuroinhibitory microenvironment, is developed. By tailoring the structural and biochemical properties of the 3D porous nanoscaffold, enhanced axonal growth from the dual-targeting therapeutic strategy in a human induced pluripotent stem cell (hiPSC)-based in vitro model of neuroinflammation is demonstrated. Moreover, nanoscaffold-based approaches promote significant axonal growth and functional recovery in vivo in a spinal cord injury model through a unique mechanism of anti-inflammation-based fibrotic scar reduction. Given the critical role of neuroinflammation and ECM microenvironments in neuroinhibitory signaling, the developed nanobiomaterial-based therapeutic intervention may pave a new road for treating CNS injuries.