Tapered chiral nanoparticles as broad-spectrum thermally stable antivirals for SARS-CoV-2 variants.

The incessant mutations of viruses, variable immune responses, and likely emergence of new viral threats necessitate multiple approaches to novel antiviral therapeutics. Furthermore, the new antiviral agents should have broad-spectrum activity and be environmentally stable. Here, we show that biocompatible tapered CuS nanoparticles (NPs) efficiently agglutinate coronaviruses with binding affinity dependent on the chirality of surface ligands and particle shape. L-penicillamine-stabilized NPs with left-handed curved apexes display half-maximal inhibitory concentrations (IC50) as low as 0.66 pM (1.4 ng/mL) and 0.57 pM (1.2 ng/mL) for pseudo-type SARS-CoV-2 viruses and wild-type Wuhan-1 SARS-CoV-2 viruses, respectively, which are about 1,100 times lower than those for antibodies (0.73 nM). Benefiting from strong NPs-protein interactions, the same particles are also effective against other strains of coronaviruses, such as HCoV-HKU1, HCoV-OC43, HCoV-NL63, and SARS-CoV-2 Omicron variants with IC50 values below 10 pM (21.8 ng/mL). Considering rapid response to outbreaks, exposure to elevated temperatures causes no change in the antiviral activity of NPs while antibodies are completely deactivated. Testing in mice indicates that the chirality-optimized NPs can serve as thermally stable analogs of antiviral biologics complementing the current spectrum of treatments.

Wood-inspired anisotropic hydrogel electrolyte with large modulus and low tortuosity realizing durable dendrite-free zinc-ion batteries.

While aqueous zinc-ion batteries exhibit great potential, their performance is impeded by zinc dendrites. Existing literature has proposed the use of hydrogel electrolytes to ameliorate this issue. Nevertheless, the mechanical attributes of hydrogel electrolytes, particularly their modulus, are suboptimal, primarily ascribed to the substantial water content. This drawback would severely restrict the dendrite-inhibiting efficacy, especially under large mass loadings of active materials. Inspired by the structural characteristics of wood, this study endeavors to fabricate the anisotropic carboxymethyl cellulose hydrogel electrolyte through directional freezing, salting-out effect, and compression reinforcement, aiming to maximize the modulus along the direction perpendicular to the electrode surface. The heightened modulus concurrently serves to suppress the vertical deposition of the intermediate product at the cathode. Meanwhile, the oriented channels with low tortuosity enabled by the anisotropic structure are beneficial to the ionic transport between the anode and cathode. Comparative analysis with an isotropic hydrogel sample reveals a marked enhancement in both modulus and ionic conductivity in the anisotropic hydrogel. This enhancement contributes to significantly improved zinc stripping/plating reversibility and mitigated electrochemical polarization. Additionally, a durable quasi-solid-state Zn//MnO2 battery with noteworthy volumetric energy density is realized. This study offers unique perspectives for designing hydrogel electrolytes and augmenting battery performance.

Biolistic delivery of liposomes protected in metal-organic frameworks.

Needle-and-syringe-based delivery has been the commercial standard for vaccine administration to date. With worsening medical personnel availability, increasing biohazard waste production, and the possibility of cross-contamination, we explore the possibility of biolistic delivery as an alternate skin-based delivery route. Delicate formulations like liposomes are inherently unsuitable for this delivery model as they are fragile biomaterials incapable of withstanding shear stress and are exceedingly difficult to formulate as a lyophilized powder for room temperature storage. Here we have developed a approach to deliver liposomes into the skin biolistically-by encapsulating them in a nano-sized shell made of Zeolitic Imidazolate Framework-8 (ZIF-8). When encapsulated within a crystalline and rigid coating, the liposomes are not only protected from thermal stress, but also shear stress. This protection from stressors is crucial, especially for formulations with cargo encapsulated inside the lumen of the liposomes. Moreover, the coating provides the liposomes with a solid exterior that allows the particles to penetrate the skin effectively. In this work, we explored the mechanical protection ZIF-8 provides to liposomes as a preliminary investigation for using biolistic delivery as an alternative to syringe-and-needle-based delivery of vaccines. We demonstrated that liposomes with a variety of surface charges could be coated with ZIF-8 using the right conditions, and this coating can be just as easily removed-without causing any damage to the protected material. The protective coating prevented the liposomes from leaking cargo and helped in their effective penetration when delivered into the agarose tissue model and porcine skin tissue.

Transient inhibition of lysosomal functions potentiates nucleic acid vaccines.

Nucleic acid vaccines have shown promising results in the clinic against infectious diseases and cancers. To robustly improve the vaccine efficacy and safety, we developed an approach to increase the intracellular stability of nucleic acids by transiently inhibiting lysosomal function in targeted tissues using sucrose. To achieve efficient and localized delivery of sucrose in animals, we designed a biomimetic lipid nanoparticle (LNP) to target the delivery of sucrose into mouse muscle cells. Using this approach, viral antigen expression in mouse muscle after DNA vaccination was substantially increased and prolonged without inducing local or systemic inflammation or toxicity. The same change in antigen expression would be achieved if the vaccine dose could be increased by 3,000 folds, which is experimentally and clinically impractical due to material restrictions and severe toxicity that will be induced by such a high dose of nucleic acids. The increase in antigen expression augmented the infiltration and activation of antigen-presenting cells, significantly improved vaccine-elicited humoral and T cell responses, and fully protected mice against the viral challenge at a low dose of vaccine. Based on these observations, we conclude that transient inhibition of lysosome function in target tissue by sucrose LNPs is a safe and potent approach to substantially improve nucleic acid-based vaccines.

Application of biomimetic nanovaccines in cancer immunotherapy: A useful strategy to help combat immunotherapy resistance.

Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.

Photoacoustic image-guided biomimetic nanoparticles targeting rheumatoid arthritis.

The high level of reactive oxygen species (ROS) in the rheumatoid arthritis (RA) microenvironment (RAM) and its persistent inflammatory nature can promote damage to joints, bones, and the synovium. Targeting strategies that integrate effective RAM regulation with imaging-based monitoring could lead to improvements in the diagnosis and treatment of RA. Here, we report the combined use of small interfering RNAs (siRNAsT/I) and Prussian blue nanoparticles (PBNPs) to silence the expression of proinflammatory cytokines TNF-α/IL-6 and scavenge the ROS associated with RAM. To enhance the in vitro and in vivo biological stability, biocompatibility, and targeting capability of the siRNAsT/I and PBNPs, macrophage membrane vesicles were used to prepare biomimetic nanoparticles, M@P-siRNAsT/I. The resulting constructs were found to suppress tumor necrosis factor-α/interleukin-6 expression and overcome the hypoxic nature of RAM, thus alleviating RA-induced joint damage in a mouse model. The M@P-siRNAsT/I of this study could be monitored via near-infrared photoacoustic (PA) imaging. Moreover, multispectral PA imaging without the need for labeling permitted the real-time evaluation of M@P-siRNAsT/I as a putative RA treatment. Clinical microcomputed tomography and histological analysis confirmed the effectiveness of the treatment. We thus suggest that macrophage-biomimetic M@P-siRNAsT/I and their analogs assisted by PA imaging could provide a new strategy for RA diagnosis, treatment, and monitoring.

Highly Efficient Fabrication of Biomimetic Nanoscaled Tendrils for High-Performance PM0.3 Air Filters.

Particulate matter pollution has become a serious public health issue, especially with the outbreak of new infectious diseases. However, most existing air filtration materials face challenges such as being too bulky, having high resistance, and a trade-off between filtration efficiency and air permeability. Here, a unique electro-blown spinning technique is used to prepare an air filter made of biomimetic nanoscaled tendril nonwovens (Nano-TN). The introduction of an airflow field significantly increases the whipping frequency and the strain mismatch of composite jets, achieving large-scale and highly efficient preparation of Nano-TN. The resultant Nano-TN has an ultrahigh porosity (97%) and a small pore size (2.9 µm). At the same filtration level, its air resistance is 37% lower than that of traditional straight nanofibrous nonwovens and has a higher dust-holding capacity. Moreover, compared with traditional three-dimensional air filters, the Nano-TN filter is thinner, offering tremendous application prospects in various environmental purification and personal protection fields.

Multi-biomimetic Double Interlaced Wetting Janus Surface for Efficient Fog Collection.

Various methods to solve water scarcity have attracted increasing attention. However, most existing water harvesting schemes have a high demand for preparation methods and costs. Here, a multi-biomimetic double interlaced wetting Janus surface (DIWJS) was prepared by laser for effective fog collection. The as-prepared surfaces are composed of superhydrophilic points/hydrophobic substrates on the A-side and superhydrophilic stripes/hydrophobic substrates on the B-side. The interlaced wettability and superhydrophilic points on the A side are conducive to capture and permeation of droplets. The superhydrophilic stripes and interlaced wettability on the B-side are conducive to transportation and shedding of droplets. Therefore, the overall fog collection process is accelerated. The proposal of smart farm model validates broad application prospects of DIWJS. This work provides an advanced and multi-biomimetic surface and provides important insights for green, low-cost, and versatile strategies to solve water scarcity issues.

Virus-Inspired Glucose and Polydopamine (GPDA)-Coating as an Effective Strategy for the Construction of Brain Delivery Platforms.

The ability of drugs to cross the blood-brain barrier (BBB) is crucial for treating central nervous system (CNS) disorders. Inspired by natural viruses, here we report a glucose and polydopamine (GPDA) coating method for the construction of delivery platforms for efficient BBB crossing. Such platforms are composed of nanoparticles (NPs) as the inner core and surface functionalized with glucose-poly(ethylene glycol) (Glu-PEG) and polydopamine (PDA) coating. Glu-PEG provides selective targeting of the NPs to brain capillary endothelial cells (BCECs), while PDA enhances the transcytosis of the NPs. This strategy is applicable to gold NPs (AuNPs), silica, and polymeric NPs, which achieves as high as 1.87% of the injected dose/g of brain in healthy brain tissues. In addition, the GPDA coating manages to deliver NPs into the tumor tissue in the orthotopic glioblastoma model. Our study may provide a universal strategy for the construction of delivery platforms for efficient BBB crossing and brain drug delivery.

Kink-Controlled Gold Nanoparticles for Electrochemical Glucose Oxidation.

Enzymes in nature efficiently catalyze chiral organic molecules by elaborately tuning the geometrical arrangement of atoms in the active site. However, enantioselective oxidation of organic molecules by heterogeneous electrocatalysts is challenging because of the difficulty in controlling the asymmetric structures of the active sites on the electrodes. Here, we show that the distribution of chiral kink atoms on high-index facets can be precisely manipulated even on single gold nanoparticles; and this enabled stereoselective oxidation of hydroxyl groups on various sugar molecules. We characterized the crystallographic orientation and the density of kink atoms and investigated their specific interactions with the glucose molecule due to the geometrical structure and surface electrostatic potential.

Flexible Multimodal Sensing System Based on a Vertical Stacking Strategy for Efficiently Decoupling Multiple Signals.

Multisensory integration enables the simultaneous perception of multiple environmental stimuli while minimizing size and energy consumption. However, conventional multifunctional integration in flexible electronics typically requires large-scale horizontal sensing arrays (such as flexible printed circuit boards), posing decoupling complexities, tensile strain limitation, and spatial constraints. Herein, a fully flexible multimodal sensing system (FMSS) is developed by coupling biomimetic stretchable conductive films (BSCFs) and strain-insensitive communication interfaces using a vertical stacking integration strategy. The FMSS achieves vertical integration without additional adhesives, and it can incorporate individual sensing layers and stretchable interconnects without any essential constraint on their deformations. Accordingly, the temperature and pressure are precisely decoupled simultaneously, and tensile stress can be accurately discerned in different directions. This vertical stacking integration strategy is expected to offer a new approach to significantly streamline the design and fabrication of multimodal sensing systems and enhance their decoupling capabilities.

Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy.

BACKGROUND: Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. METHODS: NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. RESULTS: We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. CONCLUSIONS: These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.

Biomimetic delivery of emodin via macrophage membrane-coated UiO-66-NH2 nanoparticles for acute pancreatitis treatment.

Acute pancreatitis (AP) is a severe inflammatory condition with a rising incidence and high mortality rates, especially in severe cases. Emodin (ED), known for its potent anti-inflammatory properties, holds promise in addressing AP. However, its clinical application is hindered by limitations such as low bioavailability and insufficient target specificity. Herein, we developed a novel drug delivery system using macrophage membrane-coated UiO-66-NH2 nanoparticles loaded with ED (MVs-UiO-ED). UiO-66-NH2 was successfully synthesized and characterized, revealing an octahedral structure with a suitable size distribution. The successful loading of ED onto UiO-66-NH2 was confirmed by ultraviolet and infrared spectroscopy. Subsequently, MVs-UiO-ED was prepared by coating macrophage membrane-derived vesicles onto UiO-ED, resulting in a biomimetic delivery system. In vitro release studies demonstrated that MVs-UiO-ED exhibited a sustained-release profile, indicating its potential for prolonged drug circulation. An AP mouse model was established to evaluate the therapeutic efficacy of MVs-UiO-ED. Compared with the model group, MVs-UiO-ED significantly reduced serum levels of α-amylase and lipase, two indicators of pancreatitis severity. Furthermore, histopathological examinations revealed that MVs-UiO-ED ameliorated pancreatic tissue damage. This study underscores the potential of MVs-UiO-ED as an effective therapeutic approach for AP.

Leaf-Inspired Hetero-Structure WS2/WO3 In Situ Embedded on Pomelo Peel Derived Carbon for Supercapacitor and Capacitive Deionization.

Composite materials have occupied a reliable position in electrochemical energy storage and conversion due to their double electric layer and pseudocapacitance. In this work, a leaf-like heterostructure composite, obtained by peeling - carbonizing - in situ sulfuration/oxidation approach for the first time, is investigated as electrode material for electrochemical capacitance behavior. The thin and highly active transition metal WS2 acts as an energetic "blade" to trap free ions, which are then transported across the material through a strong "tendon skeleton" WO3. The derived carbon PPC with a large aspect ratio holds up the overall leaf structure, also as a "warehouse" for ion storage, thus enhancing the conductivity and wettability of the material. The above three (WS2+WO3+PPC) synergistically provide outstanding double-layer capacitance and pseudocapacitance. In particular, the vacancy defects, constructed at the heterogenous interface from WS2-WO3 in situ growth, can still achieve superior ion absorption/desorption ability even under large current density and high concentration brackish solution.

Spontaneous Fusion of Core-Shell Nanocapsules with Oil Cores and Oppositely Charged Polysaccharide Shells.

Polymer nanocapsules with hydrophobic cores are promising candidates for nanoreactors to carry out (bio)chemical reactions mimicking the performance of natural cellular systems. Their architecture allows reagents to be encapsulated in the cores enabling reactions to proceed in confined environments in a controlled, and efficient manner. Polysaccharide-shell oil-core nanocapsules are proposed here as facile mergeable nanoreactors. Spontaneous fusion of oppositely charged polysaccharide capsules is demonstrated for the first time. Such capsules are formed and easily loaded with reagents by nanoemulsification of an aqueous solution of hydrophobically modified polysaccharides (chitosan, hyaluronate) and oleic acid with dissolved desired hydrophobic compounds. Efficient fusion of the formed nanocapsules dispersed in an aqueous medium at optimized conditions (pH, ionic strength) is followed using fluorescence microscopy by labeling both their cores and shells with fluorescent dyes. As a proof of concept, a model fluorogenic synthesis is also realized by fusing the capsules containing separated reagents and the catalyst. The nanocapsules and fusion process developed here establish a platform for realization of versatile reactions in a confined environment including model studies on biologically relevant processes taking place in natural systems.

Amino-Induced Modulation of Electronic State and Neighboring Site Distance through Second Shell Boosted Catecholase-Mimicking Activity of Electron-Rich Cu Center.

Boosting the biomimetic catalytic activity of nanozyme is important for its potential application. One common strategy to achieve this goal mainly focused on manipulating the electronic state of metal site through the first coordination shell to modulate the adsorption/desorption strength of related reactant, intermediate and/or product, but remained challenging. Taking Cu-based catecholase-mimicking nanozyme for example, this work herein reports a different strategy involving amino-induced modulation of electronic state through the second shell to raise the electron density of Cu site, which further triggers the repulsion effect between neighboring geminal Cu centers to increase the Cu─Cu distance. The resulting nanozyme with electron-rich Cu site (DT-Cu) presents a lower work function and an upshifted d-band center in comparison with its counterpart (i.e., relatively electron-deficient TA-Cu), which promotes the electron transfer and enhances the adsorption strengths of Cu site for O2, catechol and H2O2 intermediate. The longer Cu─Cu distance of DT-Cu accelerated the O─O bond dissociation of H2O2 intermediate. This expedites the oxygen reduction process during catecholase-like catalysis, which together with the enhanced O2/H2O2/catechol adsorption corporately boosts the catecholase-like activity of DT-Cu.

Visible Light-Gating Responsive Nanochannel for Controlled Release of the Fungicide.

Fungicides have been widely used to protect crops from the disease of pythium aphanidermatum (PA). However, excessive use of synthetic fungicides can lead to fungal pathogens developing microbicide resistance. Recently, biomimetic nano-delivery systems have been used for controlled release, reducing the overuse of fungicides, and thereby protecting the environment. In this paper, inspired by chloroplast membranes, visible light biomimetic channels are constructed by using retinal, the main component of green pigment on chloroplasts in plants, which can achieve the precise controlled release of the model fungicide methylene blue (MB). The experimental results show that the biomimetic channels have good circularity after and before light conditions. In addition, it is also found that the release of MB in visible light by the retinal-modified channels is 8.78 µmol·m-2·h-1, which is four times higher than that in the before light conditions. Furthermore, MB, a bactericide drug model released under visible light, can effectively inhibit the growth of PA, reaching a 97% inhibition effect. The biomimetic nanochannels can realize the controlled release of the fungicide MB, which provides a new way for the treatment of PA on the leaves surface of cucumber, further expanding the application field of biomimetic nanomembrane carrier materials.

Biomimetic Mineralization Synthesis of Flower-Like Cobalt Selenide/Reduced Graphene Oxide for Improved Electrochemical Deionization.

Rationally and precisely tuning the composition and structure of materials is a viable strategy to improve electrochemical deionization (EDI) performances, which yet faces enormous challenges. Herein, an eco-friendly biomimetic mineralization synthetic strategy is developed to synthesize the flower-like cobalt selenide/reduced graphene oxide (Bio-CoSe2 /rGO) composites and used as advanced sodium ion adsorption electrodes. Benefiting from the slow and controllable reaction kinetics provided by the biomimetic mineralization process, the flower-like CoSe2 is uniformly constructed in the rGO, which is endowed with robust architecture, substantial adsorption sites and rapid charge/ion transport. The Bio-CoSe2 /rGO electrode yields the maximum salt adsorption capacity and salt adsorption rate of 56.3 mg g-1 and 5.6 mg g-1 min-1 respectively, and 92.5% capacity retention after 60 cycles. These results overmatch the pristine CoSe2 and irregular granular CoSe2 /rGO synthesized by a hydrothermal method, proving the structural superiority of the Bio-CoSe2 /rGO composites. Furthermore, the in-depth adsorption kinetics study indicates the chemisorption nature of sodium ion adsorption. The structures of the Bio-CoSe2 /rGO composites after long term EDI cycles are intensively studied to unveil the mechanism behind such superior EDI performances. This study offers one effective method for constructing advanced EDI electrodes, and enriches the application of the biomimetic mineralization synthetic strategy.

Engineering Zinc-Organic Frameworks-Based Artificial Carbonic Anhydrase with Ultrafast Biomimetic Centers for Efficient Hydration Reactions.

Constructing effective and robust biocatalysts with carbonic anhydrase (CA)-mimetic activities offers an alternative and promising pathway for diverse CO2-related catalytic applications. However, there is very limited success has been achieved in controllably synthesizing CA-mimetic biocatalysts. Here, inspired by the 3D coordination environments of CAs, this study reports on the design of an ultrafast ZnN3-OH2 center via tuning the 3D coordination structures and mesoporous defects in a zinc-dipyrazolate framework to serve as new, efficient, and robust CA-mimetic biocatalysts (CABs) to catalyze the hydration reactions. Owing to the structural advantages and high similarity with the active center of natural CAs, the double-walled CAB with mesoporous defects displays superior CA-like reaction kinetics in p-NPA hydrolysis (V0 = 445.16 nM s-1, Vmax = 3.83 µM s-1, turnover number: 5.97 × 10-3 s-1), which surpasses the by-far-reported metal-organic frameworks-based biocatalysts. This work offers essential guidance in tuning 3D coordination environments in artificial enzymes and proposes a new strategy to create high-performance CA-mimetic biocatalysts for broad applications, such as CO2 hydration/capture, CO2 sensing, and abundant hydrolytic reactions.

Bone-Targeted Biomimetic Nanogels Re-Establish Osteoblast/Osteoclast Balance to Treat Postmenopausal Osteoporosis.

Insufficient bone formation and excessive bone resorption caused by estrogen deficiency are the major factors resulting in the incidence of postmenopausal osteoporosis (PMOP). The existing drugs usually fail to re-establish the osteoblast/osteoclast balance from both sides and generate side-effects owing to the lack of bone-targeting ability. Here, engineered cell-membrane-coated nanogels PNG@mR&C capable of scavenging receptor activator of nuclear factor-κB ligand (RANKL) and responsively releasing therapeutic PTH 1-34 in the bone microenvironment are prepared from RANK and CXCR4 overexpressed bone mesenchymal stem cell (BMSC) membrane-coated chitosan biopolymers. The CXCR4 on the coated-membranes confer bone-targeting ability, and abundant RANK effectively absorb RANKL to inhibit osteoclastogenesis. Meanwhile, the release of PTH 1-34 triggered by osteoclast-mediated acid microenvironment promote osteogenesis. In addition, the dose and frequency are greatly reduced due to the smart release property, prolonged circulation time, and bone-specific accumulation. Thus, PNG@mR&C exhibits satisfactory therapeutic effects in the ovariectomized (OVX) mouse model. This study provides a new paradigm re-establishing the bone metabolic homeostasis from multitargets and shows great promise for the treatment of PMOP.