Journal of materials chemistry. B最新文献

Reactive oxygen species (ROS)-mediated immunogenic cell death (ICD) is crucial in radioimmunotherapy by boosting innate antitumor immunity. However, the hypoxic tumor microenvironment (TME) often impedes ROS production, limiting the efficacy of radiotherapy. To tackle this challenge, a combination therapy involving radiotherapy and immune checkpoint blockade (ICB) with anti-programmed death-ligand 1 (PD-L1) has been explored to enhance antitumor effects and reprogram the immunosuppressive TME. Here, we introduce a novel PD-L1 aptamer-functionalized nanoradiosensitizer designed to augment radiotherapy by increasing X-ray deposition specifically at the tumor site. This innovative X-ray-activated nanoradiosensitizer, comprising gold-MnO₂ nanoflowers, efficiently enhances ROS generation under single low-dose radiation and repolarizes M2-like macrophages, thereby boosting antitumor immunity. Additionally, the ICB inhibitor BMS-202 synergizes with the PD-L1 aptamer-assisted nanoradiosensitizer to block the PD-L1 receptor, promoting T cell activation. Furthermore, this nanoradiosensitizer exhibits exceptional photothermal conversion efficiency, amplifying the ICD effect. The PD-L1-targeted nanoradiosensitizer effectively inhibits primary tumor growth and eliminates distant tumors, underscoring the potential of this strategy in optimizing both radioimmunotherapy and photothermal therapy.

Microtubules are highly dynamic structures, and their dynamic instability is indispensable for not only cell growth and movement, but also stress responses, such as endoplasmic reticulum (ER) stress. Docetaxel, a microtubule targeting agent (MTA), is the first-line drug for cancer treatment by simultaneously promoting microtubule dysregulation- and ER stress-induced cell death. However, it also causes adverse effects and drug resistance, especially in triple-negative breast cancer (TNBC) with a poor prognosis and high mortality rate. In this study, we developed a peptide-templated gold nanocluster, namely GA. GA significantly sensitizes TNBC cells to docetaxel, causing severe cell death. This effect is further validated by a 3D tumor spheroid model. Mechanistically, GA disrupted microtubule dynamic instability, meanwhile promoting PERK-mediated ER stress. Interestingly, ER stress inhibitors profoundly suppressed microtubule dysregulation, suggesting a retrograde regulation of ER stress on microtubules. In vivo, the combined administration of docetaxel and GA significantly suppresses tumor growth while docetaxel alone cannot. GA similarly elevated the level of caspases and PERK within tumors as in vitro. Importantly, GA treatment also profoundly promoted the production of anti-tumor inflammatory cytokines. Collectively, we developed an ER-microtubule regulatory nanomaterial that enhanced the therapeutic effect of docetaxel by elevating tumor cell death and anti-tumor cytokine production, providing a potential supplemental strategy for TNBC treatment.

Although chemotherapy with magnetic nanocarriers has witnessed significant advancement in the field of cancer treatment, multimodal diagnosis and combinatorial therapy using a single nanoplatform will have much better efficacy in achieving superior results. Herein, we constructed a smart theranostic system by combining pH-sensitive tartaric acid-stabilized Fe₃O₄ magnetic nanocarriers (TMNCs) with SPECT imaging and a chemotherapeutic agent for image-guided chemo-hyperthermia therapy. The carboxyl-enriched exteriors of TMNCs provided sites for the conjugation of a chemotherapeutic drug (doxorubicin hydrochloride, DOX) and radiolabeling (¹⁴¹Ce). The usage of 145.4 keV gamma rays made this platform an ideal choice for in vivo SPECT-CT imaging, showing the retention of the nanoformulation in the tumor site even after 28 days. Further, TMNCs showed a very high transverse relaxation rate (r₂) of 171 mM^-1 s^-1, which is higher than that of clinically approved magnetic resonance imaging (MRI) contrast agents such as ferumoxtran (65 mM^-1 s^-1) and ferumoxides (120 mM^-1 s^-1). Further, the developed drug-loaded hybrid platform showed significantly higher cytotoxicity towards breast cancer cells, which was augmented by in vitro magnetic hyperthermia. Bright-field microscopy and cell cycle analysis suggested that cell death occurred through induction of G2-M arrest and subsequent apoptosis. These findings clearly suggest the potential of the developed hybrid nanoplatform for image-guided combination therapy.

Improving our ability to treat skeletal defects is a critical medical challenge that necessitates the development of new biomaterials. One promising approach involves the use of degradable polymer microparticles with an interconnected internal porosity. Here, we employed a double emulsion to generate such round microparticles (also known as microspheres) from a polycaprolactone-based polymerised high internal phase emulsion (polyHIPE). These microspheres effectively supported the growth of mesenchymal progenitors over a 30-day period, and when maintained in osteogenic media, cells deposited a bone-like extracellular matrix, as determined by histological staining for calcium and collagen. Interestingly, cells with an osteocyte-like morphology were observed within the core of the microspheres indicating the role of a physical environment comparable to native bone for this phenotype to occur. At later timepoints, these cultures had significantly increased mRNA expression of the osteocyte-specific markers dentin matrix phosphoprotein-1 (Dmp-1) and sclerostin, with sclerostin also observed at the protein level. Cells pre-cultured on porous microspheres exhibited enhanced survival rates compared to those pre-cultured on non-porous counterparts when injected. Cells precultured on both porous and non-porous microspheres promoted angiogenesis in a chorioallantoic membrane (CAM) assay. In summary, the polycaprolactone polyHIPE microspheres developed in this study exhibit significant promise as an alternative to traditional synthetic bone graft substitutes, offering a conducive environment for cell growth and differentiation, with the potential for better clinical outcomes in bone repair and regeneration.

Nerve guide conduits (NGCs) offer a promising alternative to traditional tools for regenerating peripheral nerves. The efficacy of nerve regeneration and functional recovery is heavily dependent on the electrical, chemical, and physical properties of NGCs. A bionic melt electrowriting (MEW) NGC loaded with placental derived mesenchymal stem cells (PDMSCs) has been developed. Our study introduces a novel approach by utilizing Schwann cells induced from placental mesenchymal stem cells (PDMSCs), showcasing their potential in enhancing nerve regeneration when integrated with conductive nerve guidance conduits. Schwann cells (SCs) are crucial for nerve regeneration, and while various stem cells, including bone marrow stromal cells (BMSCs), have been investigated as sources of SCs for NGC loading, they are often limited by ethical concerns and restricted availability. PDMSCs, however, offer the advantages of widespread sourcing and unique ability to differentiate into SCs, making them an attractive alternative for NGC applications. This NGC utilizes an electrostatic direct writing technique employing polycaprolactone (PCL) for the sheath and a crimped fiber scaffold made of polypyrrole (PPY) incorporated with PDMSCs for its internal structure. The bionic PC-NGC loaded with PDMSCs exhibits favorable characteristics including permeability, mechanical stability, and electrical conductivity. The PPY component effectively transmits physiological nerve signals, thereby promoting nerve regeneration, while the PDMSCs differentiate into Schwann cells, creating a conducive environment for nerve regeneration. This research innovatively combines PDMSCs, known for their wide availability and SC differentiation potential, with a bionic NGC to enhance the treatment of peripheral nerve injuries (PNIs). In vitro evaluations have confirmed the excellent biocompatibility of the materials used. Animal experiments using a rat model with sciatic nerve injury demonstrated that the PC-NGC significently facilitated peripheral nerve regeneration. This was evidenced by improvements in axonal myelination, increased muscle mass, enhanced sciatic nerve function index, and positive electrophysiological findings. These outcomes are comparable to those achieved through autologous transplantation. Characterized by its layered oriented fibers, the bionic PC-NGC integrates multi-scale and multifunctional biomaterials with PDMSCs to effectively address peripheral nerve injuries (PNIs). The use of this printed NGC stimulates neuronal cell growth, thereby accelerating nerve regeneration. This innovative approach in tissue engineering presents a promising clinical treatment strategy for PNIs.

The ability of polymeric assemblies to undergo programmable cascades of mesophase transitions is prevalent in many systems in nature, where structural and functional features are tightly bound to maximize activity. In this study, we have examined the ability to program the mesophase transition rates of co-assembled enzyme-responsive polymeric micelles, through fine adjustments of the hydrophobicity of their amphiphilic components. We have utilized the different reactivities of di- and tri-block amphiphiles toward enzymatic degradation as a tool for programming formulations to undergo sequential enzymatically induced transitions from micelles to hydrogels and finally to dissolved polymers. By varying the aliphatic end-groups of PEG-dendron di-block and tri-block amphiphiles, we could demonstrate the remarkable impact of minor modifications to the di-block amphiphiles' structure and hydrophobicity on the transition rates between the different mesophases, ranging from a few hours to a week. Additionally, the study reveals how altering the relative hydrophobicity of its amphiphilic components influences the formulation ratio and enzymatic selectivity, as well as the stability and degradation rate of the resulting hydrogels. The findings underscore the importance of molecular architecture and hydrophobicity as key parameters in the design of programmable enzyme-responsive polymeric assemblies, offering insights into the ability to precisely control multi-step mesophase transitions for tailored functionality.

It remains a challenge to effectively regulate the complicated microenvironment during the wound healing process. The optimization of synergistic action of angiogenesis and inflammation is considered critical for quicker scarless wound regeneration. Here, the silk nanofiber (SNF) acts as a multifunctional carrier to load hydrophobic asiaticoside (AC) and hydrophilic Mg²⁺, and also serves as an element to assemble injectable hydrogels, forming a bioactive matrix with improved angiogenic and anti-inflammatory capacities (SNF-AC-Mg). Mg²⁺ and AC distributed homogeneously inside the silk nanofiber hydrogels without compromising the mechanical performance. Both Mg²⁺ and AC released slowly to continuously tune both angiogenic and inflammatory behaviors. The hydrogels exhibited good biocompatibility, inflammation inhibition, and pro-angiogenic properties in vitro, suggesting the synergistic bioactivity of AC and Mg²⁺. In vivo analysis revealed that the synergistic action of AC and Mg²⁺ resulted in better M2-type polarization of macrophages and angiogenesis during the inflammatory phase, while effectively achieving the inhibition of excessive accumulation of collagen and scar formation during the remodeling phases. The quicker scarless regeneration of the defects treated with SNF-AC-Mg implies the priority of SNFs in designing bioactive niches with complicated cues, which will favor the functional recovery of different tissues in the future.

Staphylococcus aureus (S. aureus), a commensal organism found on the human skin, is commonly associated with nosocomial infections and exhibits virulence mediated by toxins and resistance to antibiotics. The global threat of antibiotic resistance has necessitated antimicrobial stewardship to improve the safe and appropriate use of antimicrobials; hence, there is an urgent demand for the advanced, cost-effective, and rapid detection of specific bacteria. In this regard, we aimed to selectively detect S. aureus using surface molecularly imprinted magnetic nanoparticles templated with a well-known biomarker protein A, specific to S. aureus. Herein, a highly selective surface molecularly imprinted polymeric thin layer was created on ∼250 nm magnetic nanoparticles (MNPs) through the immobilization of protein A to aldehyde functionalized MNPs, followed by monomer polymerization and template washing. This study employs the rational selection of monomers based on their computationally predicted binding affinity to protein A at multiple surface residues. The resulting MIPs from rationally selected monomer combinations demonstrated an imprinting factor as high as ∼5. Selectivity studies revealed MIPs with four-fold higher binding capacity (BC) to protein A than other non-target proteins, such as lysozyme and serum albumin. In addition, it showed significant binding to S. aureus, whereas negligible binding to other non-specific Gram-negative, i.e. Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), and Gram-positive, i.e. Bacillus subtilis (B. subtilis), bacteria. This MIP was employed for the capture and specific detection of fluorescently labeled S. aureus. Quantitative detection was performed using a conventional plate counting technique in a linear detection range of 10¹-10⁷ bacterial cells. Remarkably, the MIPs also exhibited approximately 100% cell recovery from milk samples spiked with S. aureus (10⁶ CFU mL^-1), underscoring its potential as a robust tool for sensitive and accurate bacterial detection in dairy products. The developed MIP exhibiting high affinity and selective binding to protein A finds its potential applications in the magnetic capture and selective detection of protein A as well as S. aureus infections and contaminations.

Lipid nanoparticles (LNPs) are commonly employed for drug delivery owing to their considerable drug-loading capacity, low toxicity, and excellent biocompatibility. Nevertheless, the formation of protein corona (PC) on their surfaces significantly influences the drug's in vivo fate (such as absorption, distribution, metabolism, and elimination) upon administration. PC denotes the phenomenon wherein one or multiple strata of proteins adhere to the external interface of nanoparticles (NPs) or microparticles within the biological milieu, encompassing ex vivo fluids (e.g., serum-containing culture media) and in vivo fluids (such as blood and tissue fluids). Hence, it is essential to claim the PC formation behaviors and mechanisms on the surface of LNPs. This overview provided a comprehensive examination of crucial aspects related to such issues, encompassing time evolution, controllability, and their subsequent impacts on LNPs. Classical studies of PC generation on the surface of LNPs were additionally integrated, and its decisive role in shaping the in vivo fate of LNPs was explored. The mechanisms underlying PC formation, including the adsorption theory and alteration theory, were introduced to delve into the formation process. Subsequently, the existing experimental outcomes were synthesized to offer insights into the research and application facets of PC, and it was concluded that the manipulation of PC held substantial promise in the realm of targeted delivery.

Tissue damage and cell death occurring during photothermal therapy (PTT) for tumors can induce an inflammatory response that is detrimental to tumor therapy. Herein, ultrathin Mo metallene nanosheets with a thickness of <5 nm prepared by liquid phase exfoliation were explored as functional hyperthermia agents for non-inflammatory ablation of tumors. The obtained Mo metallene nanosheets exhibited good photothermal conversion properties and significant reactive oxygen species (ROS) scavenging ability, thus achieving superior cancer cell ablation and anti-inflammatory effects in vitro. For in vivo experiments, 4T1 tumors were ablated while the inflammation-related cytokine levels did not obviously increase, demonstrating that the inflammatory response induced by PTT was inhibited by the anti-inflammatory properties of Mo metallene nanosheets. Moreover, Mo metallene nanosheets depicted good dispersibility and biocompatibility, beneficial for biomedical applications. This work introduces Mo metallenes as promising hyperthermia agents for non-inflammatory PTT of tumors.