Second near-infrared photothermal-amplified immunotherapy using photoactivatable composite nanostimulators.

BACKGROUND: The construction of a nanoimmune controlled-release system that spatiotemporally recognizes tumor lesions and stimulates the immune system response step by step is one of the most potent cancer treatment strategies for improving the sensitivity of immunotherapy response. RESULTS: Here, a composite nanostimulator (CNS) was constructed for the release of second near-infrared (NIR-II) photothermal-mediated immune agents, thereby achieving spatiotemporally controllable photothermal-synergized immunotherapy. CNS nanoparticles comprise thermosensitive liposomes as an outer shell and are internally loaded with a NIR-II photothermal agent, copper sulfide (CuS), toll-like receptor-9 (TLR-9) agonist, cytosine-phospho-guanine oligodeoxynucleotides, and programmed death-ligand 1 (PD-L1) inhibitors (JQ1). Following NIR-II photoirradiation, CuS enabled the rapid elevation of localized temperature, achieving tumor ablation and induction of immunogenic cell death (ICD) as well as disruption of the lipid shell, enabling the precise release of two immune-therapeutical drugs in the tumor region. Combining ICD, TLR-9 stimulation, and inhibited expression of PD-L1 allows the subsequent enhancement of dendritic cell maturation and increases infiltration of cytotoxic T lymphocytes, facilitating regional antitumor immune responses. CONCLUSION: CNS nanoparticle-mediated photothermal-synergized immunotherapy efficiently suppressed the growth of primary and distant tumors in two mouse models and prevented pulmonary metastasis. This study thus provides a novel sight into photo-controllably safe and efficient immunotherapy.

Second near-infrared photoactivatable nanomedicines for enhanced photothermal-chemodynamic therapy of cancer.

Nanomedicines have been widely used for cancer therapy, while controlling their activity for effective and safe treatment remains a big challenge. Herein, we report the development of a second near-infrared (NIR-II) photoactivatable enzyme-loaded nanomedicine for enhanced cancer therapy. Such a hybrid nanomedicine contains a thermoresponsive liposome shell loaded with copper sulfide nanoparticles (CuS NPs) and glucose oxidase (GOx). The CuS nanoparticles mediate the generation of local heat under 1064 nm laser irradiation, which not only can be used for NIR-II photothermal therapy (PTT), but also leads to the destruction of the thermal-responsive liposome shell to achieve the on-demand release of CuS nanoparticles and GOx. In a tumor microenvironment, GOx oxidizes glucose to produce hydrogen peroxide (H2O2) that acts as a medium to promote the efficacy of chemodynamic therapy (CDT) by CuS nanoparticles. This hybrid nanomedicine enables the synergetic action of NIR-II PTT and CDT to obviously improve efficacy without remarkable side effects via NIR-II photoactivatable release of therapeutic agents. Such a hybrid nanomedicine-mediated treatment can achieve complete ablation of tumors in mouse models. This study provides a promising nanomedicine with photoactivatable activity for effective and safe cancer therapy.

Ultrasound-triggered in situ gelation with ROS-controlled drug release for cartilage repair.

Cartilage defects are usually caused by acute trauma and chronic degeneration. However, it is still a great challenge to improve the repair of articular cartilage defects due to the limited self-regeneration capacity of such defects. Herein, a novel ROS-responsive in situ nanocomposite hydrogel loaded with kartogenin (KGN) and bone marrow-derived stem cells (BMSCs) was designed and constructed via the enzymatic reaction of fibrinogen and thrombin. Meanwhile, a ROS-responsive thioketal (TK)-based liposome was synthesized to load the chondrogenesis-inducing factor KGN, the bioenzyme thrombin and an ultrasound-sensitive agent PpIX. Under ultrasound stimulation, the TK-based liposome was destroyed, followed by in situ gelation of fibrinogen and thrombin. Moreover, sustained release of KGN was realized by regulating the ultrasound conditions. Importantly, ROS generation and KGN release within the microenvironment of the in situ fibrin hydrogel significantly promoted chondrogenic differentiation of BMSCs via the Smad5/mTOR signalling pathway and effectively improved cartilage regeneration in a rat articular cartilage defect model. Overall, the novel in situ nanocomposite hydrogel with ROS-controlled drug release has great potential for efficient cartilage repair.

In situ construction of a nano-structured akermanite coating for promoting bone formation and osseointegration of Ti-6Al-4V implants in a rabbit osteoporosis model.

With the aging population worldwide, osteoporosis, as an age-related bone metabolic disease, is becoming a hot issue in public health. However, it is still a great challenge to realize osteoporotic bone healing due to the alteration of the bone microenvironment in osteoporosis patients. In this study, a nano-structured akermanite (nAK) coating was in situ constructed on Ti-6Al-4V implants to improve osteoporotic bone repair. In vitro studies indicated that both the surface nano-topography and bioactive ions released from the nAK coatings promoted the proliferation, osteogenesis, angiogenesis and inhibited osteoclastogenesis of ovariectomy rabbit-derived bone marrow mesenchymal stem cells (OVX-rBMSCs). Furthermore, the nAK-coated Ti-6Al-4V implants improved new bone formation and osseointegration in an osteoporosis rabbit model in vivo. These results indicated that the AK coating with a nano-structured surface on the Ti-6Al-4V implant could synergistically promote bone formation and osseointegration for osteoporosis patients. This may be a promising strategy to improve the bone regeneration and osseointegration capability of orthopedic implants under osteoporosis conditions.

Interconnected collagen porous scaffolds prepared with sacrificial PLGA sponge templates for cartilage tissue engineering.

Interconnected pore structures of scaffolds are important to control the cell functions for cartilage tissue engineering. In this study, collagen scaffolds with interconnected pore structures were prepared using poly(D,L-lactide-co-glycolide) (PLGA) sponges as sacrificial templates. Six types of PLGA sponges of different pore sizes and porosities were prepared by the solvent casting/particulate leaching method and used to regulate the interconnectivity of the collagen scaffolds. The integral and continuous templating structure of PLGA sponges generated well-interconnected pore structures in the collagen scaffolds. Bovine articular chondrocytes cultured in collagen scaffolds showed homogenous distribution, fast proliferation, high expression of cartilaginous genes and high secretion of cartilaginous extracellular matrix. In particular, the collagen scaffold templated by the PLGA sacrificial sponge that was prepared with a high weight ratio of PLGA and large salt particulates showed the most promotive effect on cartilage tissue formation. The interconnected pore structure facilitated cell distribution, cell-cell interaction and cartilage tissue regeneration.

The synergistic promotion of osseointegration by nanostructure design and silicon substitution of hydroxyapatite coatings in a diabetic model.

Accumulating evidence indicates much higher failure rates for biomedical titanium implants in diabetic patients. This phenomenon is attributed to impaired osteoblastic function, suppressed angiogenesis capacity, and abnormal osteoclast activation in diabetic patients. Our previous study demonstrated that titanium implants coated with highly crystalline nanostructured hydroxyapatite (nHA) promoted the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone-implant osseointegration under healthy conditions. Furthermore, recent studies showed that silicon-substituted biomaterials exhibited excellent osteogenesis and angiogenesis performance while repressing osteoclastogenesis. Hence, we proposed that a combination of nanostructural modification and Si substitution might produce synergetic effects to mitigate the impaired osseointegration of bone implants under diabetes mellitus (DM) conditions. To confirm this hypothesis, titanium implants coated with highly crystalline Si-substituted nHA (Si-nHA) were successfully fabricated via atmospheric plasma spraying combined with hydrothermal treatment. An in vitro study demonstrated that compared to the original HA coating, the nHA coating improved osteogenic and angiogenic differentiation and altered the OPG/RANKL ratio of DM-BMSCs. In addition, the Si-nHA coating further enhanced cell proliferation, improved osteogenic and angiogenic differentiation, and repressed osteoclastogenesis in DM-BMSCs. An in vivo study confirmed that the titanium implants coated with nHA or Si-nHA effectively promoted bone formation and bone-implant osseointegration in a diabetic rabbit model, with the Si-nHA coating exhibiting the best stimulatory effect. Collectively, the results suggest that the nanostructured topography and Si substitution act synergistically to ameliorate the poor bone regeneration and osseointegration associated with DM. Thus, the results provide a promising coating method for dental and orthopedic applications under diabetic conditions.

Degradation and osteogenic induction of a SrHPO4-coated Mg-Nd-Zn-Zr alloy intramedullary nail in a rat femoral shaft fracture model.

Magnesium and Mg-based alloys are promising biomaterials for orthopedic implants because of their degradability, osteogenic effects, and biocompatibility. However, the drawbacks of these materials include high hydrogen gas production, unexpected corrosion resistance, and insufficient mechanical strength duration. Surface modification can protect these biomaterials and induce osteogenesis. In this work, a SrHPO4 coating was developed for our patented biodegradable Mg-Nd-Zn-Zr alloy (abbr. JDBM) through a chemical deposition method. The coating was characterized by in vitro immersion, ion release, and cytotoxicity tests, which showed a slower corrosion behavior and excellent cell viability. RNA sequencing of MC3T3E1 cells treated with SrHPO4-coated JDBM ion release test extract showed increased Tlr4, followed by the activation of the downstream PI3K/Akt signaling pathway, causing proliferation and growth of pre-osteoblasts. An intramedullary nail (IMN) was implanted in a femoral fracture rat model. Mechanical test, radiological and histological analysis suggested that SrHPO4-coated JDBM has superior mechanical properties, induces more bone formation, and decreases the degradation rate compared with uncoated JDBM and the administration of TLR4 inhibitor attenuated the new bone formation for fracture healing. SrHPO4 is a promising coating for JDBM implants, particularly for long-bone fractures.

Nano-Structure Designing Promotion Osseointegration of Hydroxyapatite Coated Ti-6Al-4V Alloy Implants in Diabetic Model.

Mammalian diabetes mellitus which contains altered microenvironment always impairs diverse cellular processes such as osteogenesis, angiogenesis and tissue regeneration via different mechanisms. For researches in materials science, modifying the ability of osteogenesis and angiogenesis in dental implants shows its significant importance. Nano-structure designing is considered as a facile strategy to improve the surface bioactivity of the implants. In this study, the nanorod-structured hydroxyapatite (HA) coatings on Ti-6Al-4V implants were facilely designed by the combination of plasma-spraying and hydrothermal treatment via varying reaction media. Intriguingly, hydrothermal treatment eliminated the glassy phase and impurity phases of HA coatings, and nanorod-structured surface was successfully constructed under hydrothermal treatment in Na3PO4 solution. Additionally, the HA coatings with nanorod-structured surface effectively promoted the adhesion and proliferation and further enhanced osteogenic differentiation of DM-rBMSCs in vitro. Moreover, the osseointegration of Ti-6Al-4V implants with nanorod-structured HA coating was also enhanced in diabetes mellitus rabbit model in vivo. Therefore, the nano-structured surface modification of HA coating on Ti-6Al-4V implants could target pathological bone loss via strengthening osteogenesis and angiogenesis and further potentially used as a therapeutic coating to promote diabetic osteointegration.