The excessive reactive oxygen species (ROS) accumulation and overactivated osteoclastogenesis in subchondral bone has proved to be a major cause of osteoarthritis (OA). Scavenging of ROS microenvironment to inhibit the osteoclastogenesis is highly valued in the therapeutic process of osteoarthritis. Despite the excellent ability of polyphenolic colloidal to scavenge reactive oxygen species and its affinity for macrophages, the preparation of polyphenolic colloidal nanoparticles is limited by the complex intermolecular forces between phenol molecules and the lack of understanding of polymerization/sol-gel chemistry. Herein, our work introduces a novel poly-tannin-phenylboronic colloidal nanoparticle (PTA) exclusively linked by ROS-responsive bondings. Nanocolloidal PTA has a uniform particle size, is easy and scalable to synthesize, has excellent scavenging of ROS, and can be slowly degraded. For in vitro experiments, we demonstrated that, PTA could eliminate ROS within RAW264.7 cells and impede osteoclastogenesis and bone resorption. RNA sequencing results of PTA-treated RAW264.7 cells further reveal the promotion of antioxidant activity and inhibition of osteoclastogenesis. For in vivo experiments, PTA could eliminate the ROS environment and reduce the number of osteoclasts in the subchondral bone, thereby alleviating the damage of subchondral bone and symptoms of osteoarthritis. Our research, by delving into the formation of polyphenol colloidal nanoparticles and validating their role in ROS scavenging to inhibit osteoclastogenesis in subchondral bone, may open new avenues for OA treatment in the future.

Due to the amphiphilic nature of phospholipids in the cell membrane, the amphipathicity of the nanomedicine plays a crucial role in the endocytosis. However, limited biological characterization methods restrict the study of the state of nanoparticles with different amphiphilicities on cell membranes. The understanding of interaction of amphiphilic particle with cell membrane is still lacking. Herein, by combining the dissipative particle dynamics (DPD) with the framework construction of mesoporous silica nanoparticles (MSNs), we demonstrate the enhanced endocytosis induced by the hydrophobicity. DPD results confirm that the presence of hydrophobic groups on the surface of nanoparticles can disturb the integrity of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane and induce activation of phospholipids to a higher energy level, thereby facilitating the wrapping of nanoparticles. To validate the simulation findings, uniform MSNs with hydrophilic pure silica framework and two types of amphiphilic MSNs with varying hydrophilic organic groups in the framework are rationally synthesized by using different silane precursors. The obtained three kinds of MSNs show similar diameter (~ 100 nm) and mesopores (~ 2 nm), but distinct hydrophobicity/hydrophilicity ratio. The phenyl-bridged MSN with a carbon content of 27.1% exhibits enhanced cellular uptake, consistent with the theoretical simulation results. This work sheds light on how the surface amphipathicity influences endocytosis through the interaction with cell membrane.

Chemodynamic therapy (CDT) based on cascade catalytic nanomedicine has emerged as a promising cancer treatment strategy. However, most of the reported cascade catalytic systems are designed based on symmetric- or co-assembly of multiple catalytic active sites, in which their functions are difficult to perform independently and may interfere with each other. Especially in cascade catalytic system that involves fragile natural-enzymes, the strong oxidation of free-radicals toward natural-enzymes should be carefully considered, and the spatial distribution of the multiple catalytic active sites should be carefully organized to avoid the degradation of the enzyme catalytic activity. Herein, a spatially-asymmetric cascade nanocatalyst is developed for enhanced CDT, which is composed by a Fe₃O₄ head and a closely connected mesoporous silica nanorod immobilized with glucose oxidase (mSiO₂-GOx). The mSiO₂-GOx subunit could effectively deplete glucose in tumor cells, and meanwhile produce a considerable amount of H₂O₂ for subsequent Fenton reaction under the catalysis of Fe₃O₄ subunit in the tumor microenvironment. Taking the advantage of the spatial isolation of mSiO₂-GOx and Fe₃O₄ subunits, the catalysis of GOx and free-radicals generation occur at different domains of the asymmetric nanocomposite, minimizing the strong oxidation of free-radicals toward the activity of GOx at the other side. In addition, direct exposure of Fe₃O₄ subunit without any shelter could further enhance the strong oxidation of free-radicals toward objectives. So, compared with traditional core@shell structure, the long-term stability and efficiency of the asymmetric cascade catalytic for CDT is greatly increased by 138%, thus realizing improved cancer cell killing and tumor restrain efficiency.

As the first-line technology, micelles play a pivotal role in in vivo delivery of theranostic agents because of their high biocompatibility and universality. However, in complex physiological environments (extreme dilution, pH, and oxidation or reduction, etc.), they generally suffer from structural instability and insufficient protection for encapsulated cargos. It is urgent to reinforce the structural stability of the micelles at the single-micelle level. By using the FDA-approved Pluronic F127 surfactants and indocyanine green (ICG) bioimaging agents as model, herein, we propose the silane-crosslinking assisted strategy to reinforce the structural stability of the single-micelle. Different from the traditional silane hydrolysis under the harsh experimental conditions (acidic, alkaline, and high temperature hydrothermal, etc.), the ICG loaded F127@SiO₂ hybrid single-micelles (ICG@H-micelles) with controllable sizes (15–35 nm) are synthesized at neutral pH and room temperature, which is crucial for the maintenance of the physicochemical properties of the encapsulated cargos. With the ultra-thin SiO₂ (< 5 nm) at hydrophilic layer of the single-micelle, the structural and fluorescence stability of ICG@H-micelles are much higher than the conventional micelle (ICG@micelles) in the simulated physiological environments of dilution, oxidation or reduction, and low pH. Because of the high structural and fluorescence stability, the ICG@H-micelles also exhibit longer duration time in the tumor and gastrointestinal tract bioimaging.