Enhancing ROS-Inducing Nanozyme through Intraparticle Electron Transport.

Iron oxide nanoparticles (IONPs) have garnered significant attention as a promising platform for reactive oxygen species (ROS)-dependent disease treatment, owing to their remarkable biocompatibility and Fenton catalytic activity. However, the low catalytic activity of IONPs is a major hurdle in their clinical translation. To overcome this challenge, IONPs of different compositions are examined for their Fenton reaction under pharmacologically relevant conditions. The results show that wüstite (FeO) nanoparticles exhibit higher catalytic activity than magnetite (Fe3 O4 ) or maghemite (γ-Fe2 O3 ) of matched size and coating, despite having a similar surface oxidation state. Further analyses suggest that the high catalytic activity of wüstite nanoparticles can be attributed to the presence of internal low-valence iron (Fe0 and Fe2+ ), which accelerates the recycling of surface Fe3+ to Fe2+ through intraparticle electron transport. Additionally, ultrasmall wüstite nanoparticles are generated by tuning the thermodecomposition-based nanocrystal synthesis, resulting in a Fenton reaction rate 5.3 times higher than that of ferumoxytol, an FDA-approved IONP. Compared with ferumoxytol, wüstite nanoparticles substantially increase the level of intracellular ROS in mouse mammary carcinoma cells. This study presents a novel mechanism and pivotal improvement for the development of highly efficient ROS-inducing nanozymes, thereby expanding the horizons for their therapeutic applications.

Low-cost compact optical spectroscopy and novel spectroscopic algorithm for point-of-care real-time monitoring of nanoparticle delivery in biological tissue models.

Objective: Real-time monitoring of nanoparticle delivery in biological models is essential to optimize nanoparticle-mediated therapies. However, few techniques are available for convenient real-time monitoring of nanoparticle concentrations in tissue samples. This work reported novel optical spectroscopic approaches for low-cost point-of-care real-time quantification of nanoparticle concentrations in biological tissue samples. Methods: Fiber probe measured diffuse reflectance can be described with a simple analytical model by introducing an explicit dependence on the reduced scattering coefficient. Relying on this, the changes on the inverse of diffuse reflectance are proportional to absorption change when the scattering perturbation is negligible. We developed this model with proper wavelength pairs and implemented it with both a standard optical spectroscopy platform and a low-cost compact spectroscopy device for near real-time quantification of nanoparticle concentrations in biological tissue models. Results: Both tissue-mimicking phantom and ex vivo tissue sample studies showed that our optical spectroscopic techniques could quantify nanoparticle concentrations in near real-time with high accuracies (less than 5% error) using only a pair of narrow wavelengths (530 nm and 630 nm). Conclusion: Novel low-cost point-of-care optical spectroscopic techniques were demonstrated for rapid accurate quantification of nanoparticle concentrations in tissue-mimicking medium and ex vivo tissue samples using optical signals measured at a pair of narrow wavelengths. Significance: Our methods will potentially facilitate real-time monitoring of nanoparticle delivery in biological models using low-cost point-of-care optical spectroscopy platforms, which will significantly advance nanomedicine in cancer research.

Iron oxide nanozymes enhanced by ascorbic acid for macrophage-based cancer therapy.

In recent years, using pharmacological ascorbic acid has emerged as a promising therapeutic approach in cancer treatment, owing to its capacity to induce extracellular hydrogen peroxide (H2O2) production in solid tumors. The H2O2 is then converted into cytotoxic hydroxyl free radicals (HO˙) by redox-active Fe2+ inside cells. However, the high dosage of ascorbic acid required for efficacy is hampered by adverse effects such as kidney stone formation. In a recent study, we demonstrated the efficient catalytic conversion of H2O2 to HO˙ by wüstite (Fe1-xO) nanoparticles (WNPs) through a heterogenous Fenton reaction. Here, we explore whether WNPs can enhance the therapeutic potential of ascorbic acid, thus mitigating its dose-related limitations. Our findings reveal distinct pH dependencies for WNPs and ascorbic acid in the Fenton reaction and H2O2 generation, respectively. Importantly, WNPs exhibit the capability to either impede or enhance the cytotoxic effect of ascorbic acid, depending on the spatial segregation of the two reagents by cellular compartments. Furthermore, our study demonstrates that treatment with ascorbic acid promotes the polarization of WNP-loaded macrophages toward a pro-inflammatory M1 phenotype, significantly suppressing the growth of 4T1 breast cancer cells. This study highlights the importance of orchestrating the interplay between ascorbic acid and nanozymes in cancer therapy and presents a novel macrophage-based cell therapy approach.

Magnetic nanocomplexes coupled with an external magnetic field modulate macrophage phenotype - a non-invasive strategy for bone regeneration.

Chronic inflammation is a major cause for the pathogenesis of musculoskeletal diseases such as fragility fracture, and nonunion. Studies have shown that modulating the immune phenotype of macrophages from proinflammatory to prohealing mode can heal recalcitrant bone defects. Current therapeutic strategies predominantly apply biochemical cues, which often lack target specificity and controlling their release kinetics in vivo is challenging spatially and temporally. We show a magnetic iron-oxide nanocomplexes (MNC)-based strategy to resolve chronic inflammation in the context of promoting fracture healing. MNC internalized pro-inflammatory macrophages, when coupled with an external magnetic field, exert an intracellular magnetic force on the cytoskeleton, which promotes a prohealing phenotype switch. Mechanistically, the intracellular magnetic force perturbs actin polymerization, thereby significantly reducing nuclear to cytoplasm redistribution of MRTF-A and HDAC3, major drivers of inflammatory and osteogenic gene expressions. This significantly reduces Nos2 gene expression and subsequently downregulates the inflammatory response, as confirmed by quantitative PCR analysis. These findings are a proof of concept to develop MNC-based resolution-centric therapeutic intervention to direct macrophage phenotype and function towards healing and can be translated either to supplement or replace the currently used anti-inflammatory therapies for fracture healing.

Preparation of bioactive ß-tricalcium phosphate microspheres as bone graft substitute materials.

In this study, ß-tricalcium phosphate (Ca3PO4, ß-TCP) microspheres with different diameters were fabricated via a solid-in-oil-in-water (S/O/W) emulsion method. After soaking in simulated body fluid (SBF), the fabricated ß-TCP microspheres were fully covered with a new bone-like apatite layer; subsequent analysis suggested that the microspheres have excellent bioactivity properties, specifically in inducing apatite deposition. The calcium release profiles of the microspheres were tested in pH7.4 Tris-HCl buffer, and results demonstrated that the Ca2+ continually released from microspheres during the two-week test period. We then co-cultured bone marrow stem cells (BMSCs) in vitro with ß-TCP microspheres, and performed SEM and confocal microscope analyses to find that ß-TCP microspheres efficiently promoted BMSC attachment and bone-related gene expression. The co-cultured BMSCs and microspheres were successfully implanted subcutaneously into nude mice for 8weeks. The H&E neo-tissue staining results showed that abundant new bone-like structures had formed between the ß-TCP microspheres, implying that ß-TCP microspheres used as a cell carrier and bone graft substitute material show highly promising potential application for irregular-shaped bone defect regeneration.