Tough, Antifreezing, and Piezoelectric Organohydrogel as a Flexible Wearable Sensor for Human-Machine Interaction.

Piezoelectric hydrogel sensors are becoming increasingly popular for wearable sensing applications due to their high sensitivity, self-powered performance, and simple preparation process. However, conventional piezoelectric hydrogels lack antifreezing properties and are thus confronted with the liability of rupture in low temperatures owing to the use of water as the dispersion medium. Herein, a kind of piezoelectric organohydrogel that integrates piezoelectricity, low-temperature tolerance, mechanical robustness, and stable electrical performance is reported by using poly(vinylidene fluoride) (PVDF), acrylonitrile (AN), acrylamide (AAm), p-styrenesulfonate (NaSS), glycerol, and zinc chloride. In detail, the dipolar interaction of the PVDF chain with the PAN chain facilitates the crystal phase transition of PVDF from the α to ß phase, which endows the organohydrogels with a high piezoelectric constant d33 of 35 pC/N. In addition, the organohydrogels are highly ductile and can withstand significant tensile and compressive forces through the synergy of the dipolar interaction and amide hydrogen bonding. Besides, by incorporating glycerol and zinc chloride, the growth of ice crystals is inhibited, allowing the organohydrogels to maintain stable flexibility and sensitivity even at -20 °C. The real-time monitoring of the pulse signal for up to 2 min indicates that the gel sensor has stable sensitivity. It is believed that our organohydrogels will have good prospects in future wearable electronics.

Microenvironment-responsive Cu-phenolic networks coated nanofibrous dressing with timely macrophage phenotype transition for chronic MRSA infected wound healing.

Methicillin-resistant Staphylococcus aureus (MRSA) infection is a pressing clinical issue that impedes wound healing. Pro-inflammatory M1 macrophages is required to clear bacteria and recruit various cell types during the initial phase of wound healing, but timing of this process is crucial. Herein, a microenvironment-responsive nanofibrous dressing capable of timely macrophage phenotype transition in vivo is constructed by coating copper ions (Cu2+)-polydopamine (PDA) networks on poly (ε-caprolactone) fiber (PCL-fiber) membrane. During the initial post-implantation period, the nanofibrous dressing show pH-sensitive Cu2+ release in the acidic infection microenvironment. The release Cu2+ have a direct killing effect on MRSA, and promote the proinflammatory M1 phenotype of macrophages to enhance the antibacterial macrophage response. Later, PDA to become a reactive oxygen species (ROS) scavenger when in microenvironments with elevated ROS levels, which conferred the dressing with an immunomodulatory activity that convert M1 macrophages into M2 macrophages. In vivo examination in an MRSA infected full-thickness skin wounds of rat model demonstrates that this dressing significantly facilitated infection eradication and wound healing through modulating local inflammatory phenotype. Overall, this study offers a simple and effective approach for timely manipulation of inflammation progression to promote infected wound healing.

Electro-mechanical coupling directs endothelial activities through intracellular calcium ion deployment.

Conversion between mechanical and electrical cues is usually considered unidirectional in cells with cardiomyocytes being an exception. Here, we discover a material-induced external electric field (Eex) triggers an electro-mechanical coupling feedback loop in cells other than cardiomyocytes, human umbilical vein endothelial cells (HUVECs), by opening their mechanosensitive Piezo1 channels. When HUVECs are cultured on patterned piezoelectric materials, the materials generate Eex (confined at the cellular scale) to polarize intracellular calcium ions ([Ca2+]i), forming a built-in electric field (Ein) opposing Eex. Furthermore, the [Ca2+]i polarization stimulates HUVECs to shrink their cytoskeletons, activating Piezo1 channels to induce influx of extracellular Ca2+ that gradually increases Ein to balance Eex. Such an electro-mechanical coupling feedback loop directs pre-angiogenic activities such as alignment, elongation, and migration of HUVECs. Activated calcium dynamics during the coupling further modulate the downstream angiogenesis-inducing eNOS/NO pathway. These findings lay a foundation for developing new ways of electrical stimulation-based disease treatment.

All-Polymer Piezoelectric Elastomer with High Stretchability, Low Hysteresis, Self-Adhesion, and UV-Blocking as Flexible Sensor.

All-polymer piezoelectric elastomers that integrate self-powered, soft, and elastic performance are attractive in the fields of flexible wearable electronics and human-machine interfaces. However, a lack of adhesion and UV-blocking performances greatly hinders the potential applications of elastomers in these emerging fields. Here, a high-performance piezoelectric elastomer with piezoelectricity, mechanical robustness, self-adhesion, and UV-resistance was developed by using poly(vinylidene fluoride) (PVDF), acrylonitrile (AN), acrylamide (AAm), and oxidized tannic acid (OTA) (named PPO). In this design, the dipole-dipole interactions between the PVDF and PAN chains promoted the content of ß-PVDF, endowing high piezoelectric coefficient (d33, 58 pC/N). Besides, high stretchability (∼500%), supercompressibility (∼98%), low Young's modulus (∼0.02 MPa), and remarkable elasticity (∼13.8% hysteresis ratio) were achieved simultaneously for the elastomers. Inspired by the mussel adhesion chemistry, the OTA containing abundant catechol and quinone groups provided high adhesion (93.26 kPa to wood) and an exceptional UV-blocking property (∼99.9%). In addition, the elastomers can produce a reliable electric signal output (Vocmax = 237 mV) and show a fast response (24 ms) when subjected to external force. Furthermore, the elastomer can be easily assembled as a wearable sensor for human physiological (body pulse and speech identification) monitoring and communication.

Stimuli-responsive electrospun nanofibers for drug delivery, cancer therapy, wound dressing, and tissue engineering.

The stimuli-responsive nanofibers prepared by electrospinning have become an ideal stimuli-responsive material due to their large specific surface area and porosity, which can respond extremely quickly to external environmental incitement. As an intelligent drug delivery platform, stimuli-responsive nanofibers can efficiently load drugs and then be stimulated by specific conditions (light, temperature, magnetic field, ultrasound, pH or ROS, etc.) to achieve slow, on-demand or targeted release, showing great potential in areas such as drug delivery, tumor therapy, wound dressing, and tissue engineering. Therefore, this paper reviews the recent trends of stimuli-responsive electrospun nanofibers as intelligent drug delivery platforms in the field of biomedicine.

Injectable Intrinsic Photothermal Hydrogel Bioadhesive with On-Demand Removability for Wound Closure and MRSA-Infected Wound Healing.

Photothermal hydrogel adhesives have yielded promising results for wound closure and infected wound treatment in recent years. However, photothermal hydrogel bioadhesives with on-demand removability without additional nanomaterials-based photothermal agents have rarely been reported in the literature. In this work, an injectable intrinsic photothermal hydrogel bioadhesive with an on-demand removal trait is developed through dynamic cross-linking of gelatin (Gel), tannic acid (TA) quinone, and borax for closing skin incisions and accelerating methicillin-resistant Staphylococcus aureus (MRSA) infected wound healing. The TA quinone containing polyphenol and quinone groups with multifunctional adhesiveness and intrinsic photothermal performance confer the hydrogel adhesive with near-infrared (NIR) responsive antibacterial activity. The cross-linking of pH-sensitive boronic ester (polyphenol-B) and Schiff base bonds endow the hydrogel with great self-healing capacity and on-demand removability. Moreover, the hydrogel possesses good biocompatibility, injectability, and hemostasis. The in vivo experiment in a rat cutaneous incision model and full-thickness MRSA-infected wound model indicate that the smart hydrogel can close wounds efficiently and treat infected ones, demonstrating its superiority in noninvasive treatment of cutaneous incisions and enhancing infected full-thickness wound healing.

Silk Fibroin Combined with Electrospinning as a Promising Strategy for Tissue Regeneration.

The development of tissue engineering scaffolds is of great significance for the repair and regeneration of damaged tissues and organs. Silk fibroin (SF) is a natural protein polymer with good biocompatibility, biodegradability, excellent physical and mechanical properties and processability, making it an ideal universal tissue engineering scaffold material. Nanofibers prepared by electrospinning have attracted extensive attention in the field of tissue engineering due to their excellent mechanical properties, high specific surface area, and similar morphology as to extracellular matrix (ECM). The combination of silk fibroin and electrospinning is a promising strategy for the preparation of tissue engineering scaffolds. In this review, the research progress of electrospun silk fibroin nanofibers in the regeneration of skin, vascular, bone, neural, tendons, cardiac, periodontal, ocular and other tissues is discussed in detail.

Soft, Super-Elastic, All-Polymer Piezoelectric Elastomer for Artificial Electronic Skin.

Piezoelectric sensors are widely used in wearable devices to mimic the functions of human skin. However, it is considerably challenging to develop soft piezoelectric materials that can exhibit high sensitivity, stretchability, super elasticity, and suitable modulus. In this study, a soft skin-like piezoelectric polymer elastomer composed of poly(vinylidene fluoride) (PVDF) and a novel elastic substrate polyacrylonitrile is prepared by combining the radical polymerization and freeze-drying processes. Dipole-dipole interaction results in the phase transition of PVDF (α phase to ß phase), which enhances the electrical and mechanical performances. Thus, we achieve a high piezoelectric coefficient (d33max = 63 pC/N), good stretchability (211.3-259.3%), super compressibility (subjected to 99% compression strain without cracking), and super elasticity (100% recovery after extreme compression) simultaneously for the elastomer. The soft composite elastomer produces excellent electrical signal output (Vocmax = 253 mV) and responds rapidly (15 ms) to stress-induced polarization effects. In addition, the elastomer-based sensor accurately detects various physiological signals such as gestures, throat vibrations, and pulse waves. The developed elastomers exhibit excellent mechanical properties and high sensitivity, which helps facilitate their application as artificial electronic skin to sense subtle external pressure in real time.

Strong Biopolymer-Based Nanocomposite Hydrogel Adhesives with Removability and Reusability for Damaged Tissue Closure and Healing.

Bioadhesives are widely used in a variety of medical settings due to their ease of use and efficient wound closure and repair. However, achieving both strong adhesion and removability/reusability is highly needed but challenging. Here, we reported an injectable mesoporous bioactive glass nanoparticle (MBGN)-incorporated biopolymer hydrogel bioadhesive that demonstrates a strong adhesion strength (up to 107.55 kPa) at physiological temperatures that is also removable and reusable. The incorporation of MBGNs in the biopolymer hydrogel significantly enhances the tissue adhesive strength due to an increased cohesive and adhesive property compared to the hydrogel adhesive alone. The detachment of bioadhesive results from temperature-induced weakening of interfacial adhesive strength. Moreover, the bioadhesive displays injectability, self-healing, and excellent biocompatibility. We demonstrate potential applications of the bioadhesive in vitro, ex vivo, and in vivo for hemostasis and intestinal leakage closure and accelerated skin wound healing compared to surgical wound closures. This work provides a novel design of strong and removable bioadhesives.

Polysaccharide Electrospun Nanofibers for Wound Healing Applications.

As a type of biological macromolecule, natural polysaccharides have been widely used in wound healing due to their low toxicity, good biocompatibility, degradability and reproducibility. Electrospinning is a versatile and simple technique for producing continuous nanoscale fibers from a variety of natural and synthetic polymers. The application of electrospun nanofibers as wound dressings has made great progress and they are considered one of the most effective wound dressings. This paper reviews the preparation of polysaccharide nanofibers by electrospinning and their application prospects in the field of wound healing. A variety of polysaccharide nanofibers, including chitosan, starch, alginate, and hyaluronic acid are introduced. The preparation strategy of polysaccharide electrospun nanofibers and their functions in promoting wound healing are summarized. In addition, the future prospects and challenges for the preparation of polysaccharide nanofibers by electrospinning are also discussed.

Wireless electrical stimulation at the nanoscale interface induces tumor vascular normalization.

Pathological angiogenesis frequently occurs in tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating tumor progression. However, traditional vascular normalization strategies are not fully effective and limited by the development of resistance. Herein, inspired by the intervention of endogenous bioelectricity in vessel formation, we propose a wireless electrical stimulation therapeutic strategy, capable of breaking bioelectric homeostasis within cells, to achieve tumor vascular normalization. Polarized barium titanate nanoparticles with high mechano-electrical conversion performance were developed, which could generate pulsed open-circuit voltage under low-intensity pulsed ultrasound. We demonstrated that wireless electrical stimulation significantly inhibited endothelial cell migration and differentiation in vitro. Interestingly, we found that the angiogenesis-related eNOS/NO pathway was inhibited, which could be attributed to the destruction of the intracellular calcium ion gradient by wireless electrical stimulation. In vivo tumor-bearing mouse model indicated that wireless electrical stimulation normalized tumor vasculature by optimizing vascular structure, enhancing blood perfusion, reducing vascular leakage, and restoring local oxygenation. Ultimately, the anti-tumor efficacy of combination treatment was 1.8 times that of the single chemotherapeutic drug doxorubicin group. This work provides a wireless electrical stimulation strategy based on the mechano-electrical conversion performance of piezoelectric nanoparticles, which is expected to achieve safe and effective clinical adjuvant treatment of malignant tumors.

Exosomes-Loaded Electroconductive Hydrogel Synergistically Promotes Tissue Repair after Spinal Cord Injury via Immunoregulation and Enhancement of Myelinated Axon Growth.

Electroconductive hydrogels are very attractive candidates for accelerated spinal cord injury (SCI) repair because they match the electrical and mechanical properties of neural tissue. However, electroconductive hydrogel implantation can potentially aggravate inflammation, and hinder its repair efficacy. Bone marrow stem cell-derived exosomes (BMSC-exosomes) have shown immunomodulatory and tissue regeneration effects, therefore, neural tissue-like electroconductive hydrogels loaded with BMSC-exosomes are developed for the synergistic treatment of SCI. These exosomes-loaded electroconductive hydrogels modulate microglial M2 polarization via the NF-κB pathway, and synergistically enhance neuronal and oligodendrocyte differentiation of neural stem cells (NSCs) while inhibiting astrocyte differentiation, and also increase axon outgrowth via the PTEN/PI3K/AKT/mTOR pathway. Furthermore, exosomes combined electroconductive hydrogels significantly decrease the number of CD68-positive microglia, enhance local NSCs recruitment, and promote neuronal and axonal regeneration, resulting in significant functional recovery at the early stage in an SCI mouse model. Hence, the findings of this study demonstrate that the combination of electroconductive hydrogels and BMSC-exosomes is a promising therapeutic strategy for SCI repair.

Tough and Highly Efficient Underwater Self-Repairing Hydrogels for Soft Electronics.

The vulnerability of hydrogel electronic materials to mechanical damage due to their soft nature has necessitated the development of self-repairing hydrogel electronics. However, the development of such material with underwater self-repairing capability as well as excellent mechanical properties for application in aquatic environments is highly challenging and has not yet been fully realized. This study designs a tough and highly efficient underwater self-repairing supramolecular hydrogel by synergistically combining weak hydrogen bonds (H-bonds) and strong dipole-dipole interactions. The resultant hydrogel has high stretchability (up to 700%) and toughness (4.45 MJ m-3 ), and an almost 100% fast strain self-recovery (10 min). The underwater healing process is rapid and autonomous (98% self-repair efficiency after 1 h of healing). Supramolecular hydrogels can be developed as soft electronic sensors for physiological signal detection (gestures, breathing, microexpression, and vocalization) and real-time underwater communication (Morse code). Importantly, the hydrogel sensor can function underwater after mechanical damage because of its highly efficient underwater self-repairing capability.

Extracellular Matrix-Based Conductive Interpenetrating Network Hydrogels with Enhanced Neurovascular Regeneration Properties for Diabetic Wounds Repair.

The critical effects that impair diabetic wound healing are characterized by poor vascularization and severe peripheral neuropathy. Current management strategies for diabetic wound healing are unsatisfactory, due to the paucity of neurovascular regeneration at the wound site. Importantly, conductivity in skin tissue is reported to be essential for modulating myriad biological processes especially vascular and nerve regeneration. Herein, an extracellular matrix (ECM)-based conductive dressing is synthesized from an interpenetrating polymer network hydrogel composed of gelatin methacryloyl, oxidized chondroitin sulfate (OCS), and OCS-polypyrrole conductive nanoparticles that can promote diabetic wound repairing by enhancing local neurovascular regeneration. The conductive hydrogels combine the advantageous features of water-swollen hydrogels with conductive polymers (CPs) to provide tissue-matching electrical conductivity and mechanical properties for neurovascular regeneration. In vitro and in vivo studies show that the conductive hydrogel can promote neurovascular regeneration by increasing intracellular Ca2+ concentration, which subsequently promotes phosphorylation of proteins in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways. Furthermore, the conductive hydrogel stimulates full-thickness diabetic wound repair on day 14 by promoting local neurovascular regeneration and collagen deposition. These findings corroborate that the ECM-based conductive interpenetrating network hydrogel dressing significantly promotes wound repairing due to its neurovascular regeneration properties, suggesting that they are suitable candidates for diabetic wound repair.

An injectable, self-healing, electroconductive extracellular matrix-based hydrogel for enhancing tissue repair after traumatic spinal cord injury.

Injectable biomaterial-based treatment is a promising strategy to enhance tissue repair after traumatic spinal cord injury (SCI) by bridging cavity spaces. However, there are limited reports of injectable, electroconductive hydrogels with self-healing properties being employed for the treatment of traumatic SCI. Hence, a natural extracellular matrix (ECM) biopolymer (chondroitin sulphate and gelatin)-based hydrogel containing polypyrrole, which imparted electroconductive properties, is developed for traumatic SCI repair. The resulting hydrogels showed mechanical (~928 Pa) and conductive properties (4.49 mS/cm) similar to natural spinal cord tissues. Moreover, the hydrogels exhibited shear-thinning and self-healing abilities, which allows it to be effectively injected into the injury site and to fill the lesion cavity to accelerate the tissue repair of traumatic SCI. In vitro, electroconductive ECM hydrogels promoted neuronal differentiation, enhanced axon outgrowth, and inhibited astrocyte differentiation. The electroconductive ECM hydrogel activated endogenous neural stem cell neurogenesis in vivo (n = 6), and induced myelinated axon regeneration into the lesion site via activation of the PI3K/AKT and MEK/ERK pathways, thereby achieving significant locomotor function restoration in rats with spinal cord injury (p < 0.001, compared to SCI group). Overall, the injectable self-healing electroconductive ECM-based hydrogels developed in this study are ideal biomaterials for treatment of traumatic SCI.

A Novel Carbon Dots/Thermo-Sensitive In Situ Gel for a Composite Ocular Drug Delivery System: Characterization, Ex-Vivo Imaging, and In Vivo Evaluation.

We developed a potential composite ocular drug delivery system for the topical administration of diclofenac sodium (DS). The novel carbon dot CDC-HP was synthesized by the pyrolysis of hyaluronic acid and carboxymethyl chitosan through a one-step hydrothermal method and then embedded in a thermosensitive in situ gel of poloxamer 407 and poloxamer 188 through swelling loading. The physicochemical characteristics of these carbon dots were investigated. The results of the in vitro release test showed that this composite ocular drug delivery system (DS-CDC-HP-Gel) exhibited sustained release for 12 h. The study of the ex vivo fluorescence distribution in ocular tissues showed that it could be used for bioimaging and tracing in ocular tissues and prolong precorneal retention. Elimination profiles in tears corresponded to the study of ex vivo fluorescence imaging. The area under the curve of DS in the aqueous humor in the DS-CDC-HP-Gel group was 3.45-fold that in the DS eye drops group, indicating a longer precorneal retention time. DS-CDC-HP with a positive charge and combined with a thermosensitive in situ gel might strengthen adherence to the corneal surface and prolong the ocular surface retention time to improve the bioavailability. This composite ocular delivery system possesses potential applications in ocular imaging and drug delivery.

A core-shell nanoplatform as a nonviral vector for targeted delivery of genes to the retina.

Retinal diseases, including age-related macular degeneration (AMD), are a major cause of blindness. Efficient delivery of therapeutic genes to retinal cells to treat retinal disease is a formidable challenge. In this study, we developed a core-shell nanoplatform composed of a core and two external layers for targeted delivery of the gene to the retina. The inner core was composed of amino acid-functionalized dendrimers and a nuclear localization signal (NLS) for DNA complexation, nuclear transport and efficient transfection. The inner core was coated in a lipid bilayer that comprised pH-sensitive lipids as the inner shell layer. Hyaluronic acid (HA)-1,2-dioleoylphosphatidylethanolamine (DOPE) as the outermost shell layer was used for retinal cell targeting. This core-shell nanoplatform was developed so that the mobility in the vitreous body of these negatively charged carriers would not be affected by their surface charge, allowing diffusion into the retina, uptake into the retinal cells via CD44-mediated internalization, and finally transport into the nucleus by the NLS. The designed nanoparticles showed safety both in vitro and in vivo and inhibited the expression of VEGF under hypoxia-mimicking conditions. In vitro angiogenesis assays exhibited significant inhibitory effects on cell migration and tube formation. The in vivo assays indicated that this nanoplatform could be delivered to the retina. Taken together, this nanoplatform has the potential to transfer gene material into the retina for the treatment of retinal diseases, including AMD. STATEMENT OF SIGNIFICANCE: It remains a challenge to develop an efficient nonviral vector for gene therapy, especially retinal gene therapy. Various barriers exist in gene delivery and the unique ocular environment, making gene delivery to the retina difficult. In this study, we designed a negatively charged core-shell nanoplatform (HD-NPPND) for the targeted delivery of gene to the retina. The developed nanoplatform possessed excellent transfection efficiency and safety both in vitro and in vivo. It efficiently delivered a gene to the retina. The results of this study suggested that this core-shell nanoplatform has the potential to deliver genes to the retina to treat retinal diseases, including age-related macular degeneration (AMD).

Self-curling electroconductive nerve dressing for enhancing peripheral nerve regeneration in diabetic rats.

Conductive scaffolds have been shown to exert a therapeutic effect on patients suffering from peripheral nerve injuries (PNIs). However, conventional conductive conduits are made of rigid structures and have limited applications for impaired diabetic patients due to their mechanical mismatch with neural tissues and poor plasticity. We propose the development of biocompatible electroconductive hydrogels (ECHs) that are identical to a surgical dressing in this study. Based on excellent adhesive and self-healing properties, the thin film-like dressing can be easily attached to the injured nerve fibers, automatically warps a tubular structure without requiring any invasive techniques. The ECH offers an intimate and stable electrical bridge coupling with the electrogenic nerve tissues. The in vitro experiments indicated that the ECH promoted the migration and adhesion of the Schwann cells. Furthermore, the ECH facilitated axonal regeneration and remyelination in vitro and in vivo through the MEK/ERK pathway, thus preventing muscle denervation atrophy while retaining functional recovery. The results of this study are likely to facilitate the development of non-invasive treatment techniques for PNIs in diabetic patients utilizing electroconductive hydrogels.

Amino acids functionalized dendrimers with nucleus accumulation for efficient gene delivery.

Gene therapy is a promising approach to many diseases, however, the barriers in the gene delivery restrict its application. Therefore, in the present study, an efficient non-viral gene vector (PRHF/N/D) for overcoming the barriers in gene delivery was prepared. The synthesized PRHF integrated the advantages of PAMAM and amino acids, which could improve the cellular uptake, enhance the endosomal escape ability and minimize cytotoxicity. To further enhance nuclear entry of carrier, the nuclear localization signal (NLS) peptide was selected to add in the PRHF/D polyplexes. The PRHF/N/D polyplexes demonstrated good condensation capacity, wonderful pDNA protection and low toxicity. Moreover, the PRHF/N/D polyplexes showed the excellent transfection efficiency than P/D. PRHF/N/D further improve transfection capability than PRHF/D in the presence of NLS. After 4 h of incubation, the mean fluorescence intensity of PRHF/N/D was also higher than the P/D and PRHF/D complexes. We then investigated the intracellular dissociation, the DNA is able to disassemble from PRHF/N/D gene carriers. Taken together, we exhibited that this PRHF/N/D polyplexes has the potential for use in the gene delivery.

Exosome-functionalized polyetheretherketone-based implant with immunomodulatory property for enhancing osseointegration.

The host immune response effecting on biomaterials is critical to determine implant fates and bone regeneration property. Bone marrow stem cells (BMSCs) derived exosomes (Exos) contain multiple biosignal molecules and have been demonstrated to exhibit immunomodulatory functions. Herein, we develop a BMSC-derived Exos-functionalized implant to accelerate bone integration by immunoregulation. BMSC-derived Exos were reversibly incorporated on tannic acid (TA) modified sulfonated polyetheretherketone (SPEEK) via the strong interaction of TA with biomacromolecules. The slowly released Exos from SPEEK can be phagocytosed by co-cultured cells, which could efficiently improve the biocompatibilities of SPEEK. In vitro results showed the Exos loaded SPEEK promoted macrophage M2 polarization via the NF-κB pathway to enhance BMSCs osteogenic differentiation. Further in vivo rat air-pouch model and rat femoral drilling model assessment of Exos loaded SPEEK revealed efficient macrophage M2 polarization, desirable new bone formation, and satisfactory osseointegration. Thus, BMSC-derived Exos-functionalized implant exerted osteoimmunomodulation effect to promote osteogenesis.