Staphylococcus aureus ( S. aureus) is a causative agent in life-threatening human diseases that afflict millions of people annually. Traditional antibiotic treatments are becoming less efficient because S. aureus can invade host cells including osteoblasts and macrophages, constituting a reservoir that is relatively protected from antibiotics that can lead to recrudescent infection. We herein report a unique intracellular antibiotic delivery nanoparticle, which is composed of (i) a mesoporous silica nanoparticle (MSN) core loaded with gentamicin, (ii) an infected microenvironment (bacterial toxin)-responsive lipid bilayer surface shell, and (iii) bacteria-targeting peptide ubiquicidin (UBI) that is immobilized on the lipid bilayer surface shell. The lipid material acts as a gate that prevents drug release before the MSNs reach the target cells or tissue, at which point they are degraded by bacterial toxins to rapidly release the drug, thus eliminating efficient bacteria. We confirm rapid drug release in the presence of bacteria in an extracellular model and observe that S. aureus growth is effectively inhibited both in vitro and in vivo of planktonic and intracellular infection. The inflammation-related gene expression in infected preosteoblast or macrophage is also downregulated significantly after treatment by the antibiotic delivery nanoparticles. The antibiotic delivery nanoparticles offer advantages in fighting intracellular pathogens and eliminating the inflammation caused by intracellular bacterial infections.

The objective was to investigate the effect of kinsenoside (Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis (OA) progression. RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium (CM) and IL-1β were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection (ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of P65 in nuclear factor-κB (NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases (MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages, promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.

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The early detection and thus treatment of breast cancer bone metastasis remain a big challenge clinically. As the most abundant cells within bone tissue, osteocytes have been found to manipulate the activity of early cancer bone metastasis by its crosstalk with cancer cells and osteoclasts. However, conventional bone-targeting nanomedicine has limited bone-lesion specificity and ignores the vital role of osteocytes during breast cancer bone metastasis. Also, it lacks detailed insight into the therapeutic mechanisms, which hinders the following translational practice. Previously, we have shown that a combination of zoledronic acid (ZA) and plumbagin (PL) synergistically alleviates cancer-induced bone destruction. Herein, we further develop a pH-responsive bone-targeting drug delivery system, i.e., the ZA-anchored bimodal mesoporous slica covered gadolinium(III) upconversion nanoparticles loaded with PL, to detect and treat bone metastasis sensitively and specifically at an early stage. This multifunctional nanosystem can target osteocytes to release PL as controlled by pH, decreasing osteocytic RANKL expression synergistically through the structural simulation of adenosine phosphate, which competitively inhibits the phosphorylation of osteocytic protein kinase-a, cAMP-response element binding protein, extracellular regulated protein kinase, and c-Jun N-terminal kinase. More importantly, by establishing a breast cancer bone metastasis mice model via intracardiac injection, we show that tumoriogenesis and osteoclastogenesis can both be attenuated significantly. We thereby realize the effective theranostics of tiny bone metastasis in breast cancer bone metastasis. Our work highlights the significance of theranostic nanomedicine and osteocyte-targeting therapy in the treatment of early bone metastasis, which could be applied in achieving efficient theranostic effects for other bone diseases.

Accumulating evidence suggests that activation of proinflammatory M1-type macrophages in the synovium plays a vital role in the progression of osteoarthritis (OA). Redundant nitric oxide (NO) and hydrogen peroxide (H 2 O 2 ) are key factors that drive macrophages to polarize to the M1 type. Herein, modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) have been synthesized. By regulating intracellular gases and reprogramming the metabolism phenotype, modified NPs transformed macrophage polarization from proinflammatory M1 to anti-inflammatory M2 phenotype. Specifically, S-methylisothiourea hemisulfate salt was loaded into ZIF-8 NPs to inhibit inducible nitric oxide synthase, hence reducing NO production. Catalase was encapsulated to catalyze the production of oxygen (O 2 ) from H 2 O 2 . Results demonstrated that modified NPs were capable of catalyzing H 2 O 2 to produce O 2 and eliminate NO, hence inhibiting hypoxia-inducible factor 1α, further rescuing mitochondrial function. Moreover, anti-CD16/32 antibody modification could prolong the retention time of NPs in knee joints of OA mice with anterior cruciate ligament transection. More significantly, modified NPs suppressed M1 macrophages and upregulated M2 macrophage infiltration in the synovium, further inhibiting cartilage degeneration. This ZIF-8 NP-based gas regulation and metabolic reprogramming strategy may pave a new avenue for OA treatment.

Current treatments for diabetic ulcers (DUs) remain unsatisfactory due to the risk of bacterial infection and impaired angiogenesis during the healing process. The increased degradation of polyubiquitinated hypoxia‐inducible factor‐1α (HIF‐1α) compromises wound healing efficacy. Therefore, the maintenance of HIF‐1α protein stability might help treat DU. Nitric oxide (NO) is an intrinsic biological messenger that functions as a ubiquitination flow repressor and antibacterial agent; however, its clinical application in DU treatment is hindered by the difficulty in controlling NO release. Here, an intelligent near‐infrared (NIR)‐triggered NO nanogenerator (SNP@MOF‐UCNP@ssPDA‐Cy7/IR786s, abbreviated as SNP@UCM) is presented. SNP@UCM represses ubiquitination‐mediated proteasomal degradation of HIF‐1α by inhibiting its interaction with E3 ubiquitin ligases under NIR irradiation. Increased HIF‐1α expression in endothelial cells by SNP@UCM enhances angiogenesis in wound sites, promoting vascular endothelial growth factor (VEGF) secretion and cell proliferation and migration. SNP@UCM also enables early detection of wound infections and ROS‐mediated killing of bacteria. The potential clinical utility of SNP@UCM is further demonstrated in infected full‐thickness DU model under NIR irradiation. SNP@UCM is the first reported HIF‐1α‐stabilizing advanced nanomaterial, and further materials engineering might offer a facile, mechanism‐based method for clinical DU management.

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