Pathogenic bacterial infections and drug resistance make it urgent to develop new antibacterial agents with targeted delivery. Here, a new targeting delivery nanosystem is designed based on the potential interaction between bacterial recognizing receptors on macrophage membranes and distinct pathogen‐associated molecular patterns in bacteria. Interestingly, the expression of recognizing receptors on macrophage membranes increases significantly when cultured with specific bacteria. Therefore, by coating pretreated macrophage membrane onto the surface of a gold–silver nanocage (GSNC), the nanosystem targets bacteria more efficiently. Previously, it has been shown that GSNC alone can serve as an effective antibacterial agent owing to its photothermal effect under near‐infrared (NIR) laser irradiation. Furthermore, the nanocage can be utilized as a delivery vehicle for antibacterial drugs since the gold–silver nanocage presents a hollow interior and porous wall structure. With significantly improved bacterial adherence, the Sa‐M‐GSNC nanosystem, developed within this study, is effectively delivered and retained at the infection site both via local or systemic injections; the system also shows greatly prolonged blood circulation time and excellent biocompatibility. The present work described here is the first to utilize bacterial pretreated macrophage membrane receptors in a nanosystem to achieve specific bacterial‐targeted delivery, and provides inspiration for future therapy based on this concept.

Abuse of antibiotics and their residues in the environment results in the emergence and prevalence of drug-resistant bacteria and leads to serious health problems. Herein, a photon-controlled antibacterial platform that can efficiently kill drug-resistant bacteria and avoid the generation of new bacterial resistance was designed by encapsulating black phosphorus quantum dots (BPQDs) and pharmaceuticals inside a thermal-sensitive liposome. The antibacterial platform can release pharmaceuticals in a spatial-, temporal-, and dosage-controlled fashion because the BPQDs can delicately generate heat under near-infrared light stimulation to disrupt the liposome. This user-defined delivery of drug can greatly reduce the antibiotic dosage, thus avoiding the indiscriminate use of antibiotics and preventing the generation of superbugs. Moreover, by coupling the photothermal effect with antibiotics, this antibacterial platform achieved a synergistic photothermal-/pharmaco-therapy with significantly improved antibacterial efficiency toward drug-resistant bacteria. The antibacterial platform was further employed to treat antibiotic-resistant bacteria-caused skin abscess and it displayed excellent antibacterial activity in vivo, promising its potential clinical applications. Additionally, the antibacterial mechanism was further investigated. The developed photon-controlled antibacterial platform can open new possibilities for avoiding bacterial resistance and efficiently killing antibiotic-resistant bacteria, making it valuable in fields ranging from antiinfective therapy to precision medicine.

Macrophage activation determines the fate of biomaterials implantation. Though researches have shown that fibronectin (FN) is highly involved in integrin-induced macrophage activation on biomaterials, the mechanism of how nanosized structure affects macrophage behavior is still unknown. Here, titanium dioxide nanotube structures with different sizes are fabricated to investigate the effects of nanostructure on macrophage activation. Compared with larger sized nanotubes and smooth surface, 30 nm nanotubes exhibit considerable lesser pro-inflammatory properties on macrophage differentiation. Confocal protein observation and molecular dynamics simulation show that FN displays conformation changes on different nanotubes in a feature of "size-confined," which causes the hiding of Arg-Gly-Asp (RGD) domain on other surfaces. The matching size of nanotube with FN allows the maximum exposure of RGD on 30 nm nanotubes, activating integrin-mediated focal adhesion kinase (FAK)-phosphatidylinositol-3 kinase 𝜸 (PI3K𝜸) pathway to inhibit nuclear factor kappa B (NF-𝜿B) signaling. In conclusion, this study explains the mechanism of nanostructural-biological signaling transduction in protein and molecular levels, as well as proposes a promising strategy for surface modification to regulate immune responses on bioimplants.

Implants are widely used in medical applications and yet macrophage-mediated foreign body reactions caused by implants severely impact their therapeutic effects. Although the extensive use of multiple surface modifications has been introduced to provide some mitigation of fibrosis, little is known about how macrophages recognize the stiffness of the implant and thus influence cell behaviors. Here, we demonstrated that macrophage stiffness sensing leads to differential inflammatory activation, resulting in different degrees of fibrosis. The potential mechanism for macrophage stiffness sensing in the early adhesion stages tends to involve cell membrane deformations on substrates with different stiffnesses. Combining theory and experiments, we show that macrophages exert traction stress on the substrate through adhesion and altered membrane curvature, leading to the uneven distribution of the curvature-sensing protein Baiap2, resulting in cytoskeleton remodeling and inflammation inhibition. This study introduces a physical model feedback mechanism for early cellular stiffness sensing based on cell membrane deformation, offering perspectives for future material design and targeted therapies.

The entry of implants triggers the secretion of damage associated molecular patterns (DAMPs) that recruit dendritic cells (DCs) and results in subsequent foreign body reaction (FBR). Though several studies have illustrated that the surface accessible area (SAA) of implants plays a key role in the process of DAMPs release and absorption, the effect of SAA on the immune reaction still remains unknown. Here, a series of TiO 2 plates with different SAA is fabricated to investigate the relationship between SAA and FBR. Compared with larger SAA surface, the aggregation of DC is significantly inhibited by lower SAA surface. Total internal reflection microscopy (TIRFM) and molecular dynamic (MD) simulation show that although high mobility group box 1 (HMGB1) is adsorbed more on plates with lower SAA, the exposure ratio of cysteine (CYS) residue in HMGB1 is significantly decreased in lower SAA group. The lower exposure of CYS reduces the activation of Toll-like receptors 4 (TLR4), which down-regulates the expression of myeloid differentiation factor (Myd88)-TNF receptor associated factor 6 (TRAF6) to inhibit nuclear factor kappa B (NF-𝜿B) signaling. Generally, this study reveals the mechanism of how SAA, a nanoscale property, affects FBR from perspective of DAMPs, and provides a new direction for designing better biocompatible implants.

Mechanistic understanding of fibronectin (FN) adsorption which determines cell adhesion on cell-implant interfaces is significant for improving the osteoconduction and soft-tissue healing of implants. Here, it is shown that the adsorption behavior of FN on the titanium oxide surface (TiO 2 ) is highly relative to its Pro-His-Ser-Arg-Asn (PHSRN) peptide. FN lacking PHSRN fails to bind to surfaces, resulting in inhibited cell adhesion and spreading. Molecular dynamics simulation shows higher affinity and greater adsorption energy of PHSRN peptide with TiO 2 surface due to the stronger hydrogen bonds formed by the serine and arginine residues with O ion of the substrate. Finally, by increasing O content in TiO 2 surfaces through O ion-beam implantation, improving the cell adhesion, cell differentiation, and the subsequent biomineralization on titanium implant is realized. This study reveals the vital role of PHSRN in FN-mediated cell adhesion on implant surfaces, providing a promising new target for further tissue integration and implant success.

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Zirconium implants have gained popularity among clinicians due to their superior mechanical properties. However, zirconium implants usually perform less well in early osseointegration than titanium implants. And the degree of severity of the acute inflammation resulting from macrophage activation after implantation determines the result of the implantation. The mechanism by which zirconia implants cause more acute inflammation compared to titanium implants is currently unknown. Here, the complement activation on zirconium oxide is demonstrated, which causes differences in inflammation compared to titanium oxide. More adsorption of immunoglobulin G (IgG) and complement protein C1q together with the more efficient triggering of the complement system is shown to occur on ZrO 2 surfaces. Molecular dynamics (MD) simulations further reveal that IgG exhibits more accessible binding sites on ZrO 2 surfaces due to its hydrophobicity, leading to more efficient complement activation. Reduced inflammation of hydrophilized ZrO 2 compared to non-treated ZrO 2 demonstrates the role of hydrophobicity in the higher inflammation of ZrO 2 . The results reveal that complement activation due to conformational changes and greater adsorption of IgG and C1q on ZrO 2 triggers inflammation caused by macrophages, providing new insights for implant design and performance optimization.