Mechano-Activated Cell Therapy for Accelerated Diabetic Wound Healing.

Chronic diabetic wounds are a significant global healthcare challenge. Current strategies, such as biomaterials, cell therapies, and medical devices, however, only target a few pathological features and have limited efficacy. A powerful platform technology combining magneto-responsive hydrogel, cells, and wireless magneto-induced dynamic mechanical stimulation (MDMS) is developed to accelerate diabetic wound healing. The hydrogel encapsulates U.S. Food and Drug Administration (FDA)-approved fibroblasts and keratinocytes to achieve ∼3-fold better wound closure in a diabetic mouse model. MDMS acts as a nongenetic mechano-rheostat to activate fibroblasts, resulting in ∼240% better proliferation, ∼220% more collagen deposition, and improved keratinocyte paracrine profiles via the Ras/MEK/ERK pathway to boost angiogenesis. The magneto-responsive property also enables on-demand insulin release for spatiotemporal glucose regulation through increasing network deformation and interstitial flow. By mining scRNAseq data, a mechanosensitive fibroblast subpopulation is identified that can be mechanically tuned for enhanced proliferation and collagen production, maximizing therapeutic impact. The "all-in-one" system addresses major pathological factors associated with diabetic wounds in a single platform, with potential applications for other challenging wound types.

Suppression of cytokine release syndrome during CAR-T-cell therapy via a subcutaneously injected interleukin-6-adsorbing hydrogel.

The infusion of chimaeric antigen receptor (CAR) T cells can trigger the release of life-threatening supraphysiological levels of pro-inflammatory cytokines. However, uncertainty regarding the timing and severity of such cytokine release syndrome (CRS) demands careful monitoring of the conditions required for the administration of neutralizing antibodies. Here we show that a temperature-sensitive hydrogel conjugated with antibodies for the pro-inflammatory cytokine interleukin-6 (IL-6) and subcutaneously injected before the infusion of CAR-T cells substantially reduces the levels of IL-6 during CRS while maintaining the therapy's antitumour efficacy. In immunodeficient mice and in mice with transplanted human haematopoietic stem cells, the subcutaneous IL-6-adsorbing hydrogel largely suppressed CAR-T-cell-induced CRS, substantially improving the animals' survival and alleviating their levels of fever, hypotension and weight loss relative to the administration of free IL-6 antibodies. The implanted hydrogel, which can be easily removed with a syringe following a cooling-induced gel-sol transition, may allow for a shift in the management of CRS, from monitoring to prevention.

DNA Damage Inducer Mitoxantrone Amplifies Synergistic Mild-Photothermal Chemotherapy for TNBC via Decreasing Heat Shock Protein 70 Expression.

Patients with triple-negative breast cancer (TNBC) have the worst clinical outcomes when compared to other subtypes of breast cancer. Nanotechnology-assisted photothermal therapy (PTT) opens new opportunities for precise cancer treatment. However, thermoresistance caused by PTT, as well as uncertainty in the physiological metabolism of existing phototherapeutic nanoformulations, severely limit their clinical applications. Herein, based on the clinically chemotherapeutic drug mitoxantrone (MTO), a multifunctional nanoplatform (MTO-micelles) is developed to realize mutually synergistic mild-photothermal chemotherapy. MTO with excellent near-infrared absorption (≈669 nm) can function not only as a chemotherapeutic agent but also as a photothermal transduction agent with elevated photothermal conversion efficacy (ƞ = 54.62%). MTO-micelles can accumulate at the tumor site through the enhanced permeability and retention effect. Following local near-infrared irradiation, mild hyperthermia (<50 °C) assists MTO in binding tumor cell DNA, resulting in chemotherapeutic sensitization. In addition, downregulation of heat shock protein 70 (HSP70) expression due to enhanced DNA damage can in turn weaken tumor thermoresistance, boosting the efficacy of mild PTT. Both in vitro and in vivo studies indicate that MTO-micelles possess excellent synergetic tumor inhibition effects. Therefore, the mild-photothermal chemotherapy strategy based on MTO-micelles has a promising prospect in the clinical transformation of TNBC treatment.

Fluorescence-Amplified Origami Microneedle Device for Quantitatively Monitoring Blood Glucose.

Exploration of clinically acceptable blood glucose monitors has been engaging in the past decades, yet the ability to quantitatively detect blood glucose in a painless, accurate, and highly sensitive manner remains limited. Herein, a fluorescence-amplified origami microneedle (FAOM) device is described that integrates tubular DNA-origami nanostructures and glucose oxidase molecules into its inner network to quantitatively monitor blood glucose. The skin-attached FAOM device can collect glucose molecules in situ and transfer the input into a proton signal after the oxidase's catalysis. The proton-driven mechanical reconfiguration of DNA-origami tubes separates fluorescent molecules and their quenchers, eventually amplifying the glucose-correlated fluorescence signal. The function equation established on clinical examinees suggests that FAOM can report blood glucose in a highly sensitive and quantitative manner. In clinical blind tests, the FAOM achieves well-matched accuracy (98.70 ± 4.77%) compared with a commercial blood biochemical analyzer, fully meeting the requirements of accurate blood glucose monitoring. The FAOM device can be inserted into skin tissue in a trivially painful manner and with minimal leakage of DNA origami, substantially improving the tolerance and compliance of the blood glucose test.

Mechano-responsive hydrogel for direct stem cell manufacturing to therapy.

Bone marrow-derived mesenchymal stem cell (MSC) is one of the most actively studied cell types due to its regenerative potential and immunomodulatory properties. Conventional cell expansion methods using 2D tissue culture plates and 2.5D microcarriers in bioreactors can generate large cell numbers, but they compromise stem cell potency and lack mechanical preconditioning to prepare MSC for physiological loading expected in vivo. To overcome these challenges, in this work, we describe a 3D dynamic hydrogel using magneto-stimulation for direct MSC manufacturing to therapy. With our technology, we found that dynamic mechanical stimulation (DMS) enhanced matrix-integrin ß1 interactions which induced MSCs spreading and proliferation. In addition, DMS could modulate MSC biofunctions including directing MSC differentiation into specific lineages and boosting paracrine activities (e.g., growth factor secretion) through YAP nuclear localization and FAK-ERK pathway. With our magnetic hydrogel, complex procedures from MSC manufacturing to final clinical use, can be integrated into one single platform, and we believe this 'all-in-one' technology could offer a paradigm shift to existing standards in MSC therapy.

Dynamic Magneto-Softening of 3D Hydrogel Reverses Malignant Transformation of Cancer Cells and Enhances Drug Efficacy.

High extracellular matrix stiffness is a prominent feature of malignant tumors associated with poor clinical prognosis. To elucidate mechanistic connections between increased matrix stiffness and tumor progression, a variety of hydrogel scaffolds with dynamic changes in stiffness have been developed. These approaches, however, are not biocompatible at high temperature, strong irradiation, and acidic/basic pH, often lack reversibility (can only stiffen and not soften), and do not allow study on the same cell population longitudinally. In this work, we develop a dynamic 3D magnetic hydrogel whose matrix stiffness can be wirelessly and reversibly stiffened and softened multiple times with different rates of change using an external magnet. With this platform, we found that matrix stiffness increased tumor malignancy including denser cell organization, epithelial-to-mesenchymal transition and hypoxia. More interestingly, these malignant transformations could be halted or reversed with matrix softening (i.e., mechanical rescue), to potentiate drug efficacy attributing to reduced solid stress from matrix and downregulation of cell mechano-transductors including YAP1. We propose that our platform can be used to deepen understanding of the impact of matrix softening on cancer biology, an important but rarely studied phenomenon.

Nanoparticle-Driven Controllable Mitochondrial Regulation through Lysosome-Mitochondria Interactome.

Precise subcellular manipulation remains challenging in quantitative biological studies. After target modification and hierarchical assembly, nanoparticles can be functionalized for intracellular investigation. However, it remains unclear whether nanoparticles themselves can progressively manipulate subcellular processes, especially organellar networks. Mitochondria act as the energetic supply, whose fission dynamics are often modulated by molecular reagents. Here, using different-sized gold nanoparticles (AuNPs) as a model, we demonstrated the nanoparticle-driven controllable regulation on mitochondria. Compared with molecular reagents, AuNPs could induce size-dependent mitochondrial fission without detectable cell injury, and this process was reversible along with intracellular AuNPs' clearance. Mechanistically, it was attributed to the AuNPs-induced enhanced organelle interactome between lysosomes and mitochondria. Lysosomal accumulation of AuNPs induced lysosomal swelling and lysosomal motility alterations, promoting mitochondrial fission through the increased "kiss" events during the "kiss-and-run" moving of the lysosome-mitochondria interactome. This study highlights the fundamental understanding to fully explore the intrinsic capability of nanoparticles by engineering their basic properties. Also, it provides practical guidance to investigate the delicate nanolevel regulation on biological processes.

Integrative lymph node-mimicking models created with biomaterials and computational tools to study the immune system.

The lymph node (LN) is a vital organ of the lymphatic and immune system that enables timely detection, response, and clearance of harmful substances from the body. Each LN comprises of distinct substructures, which host a plethora of immune cell types working in tandem to coordinate complex innate and adaptive immune responses. An improved understanding of LN biology could facilitate treatment in LN-associated pathologies and immunotherapeutic interventions, yet at present, animal models, which often have poor physiological relevance, are the most popular experimental platforms. Emerging biomaterial engineering offers powerful alternatives, with the potential to circumvent limitations of animal models, for in-depth characterization and engineering of the lymphatic and adaptive immune system. In addition, mathematical and computational approaches, particularly in the current age of big data research, are reliable tools to verify and complement biomaterial works. In this review, we first discuss the importance of lymph node in immunity protection followed by recent advances using biomaterials to create in vitro/vivo LN-mimicking models to recreate the lymphoid tissue microstructure and microenvironment, as well as to describe the related immuno-functionality for biological investigation. We also explore the great potential of mathematical and computational models to serve as in silico supports. Furthermore, we suggest how both in vitro/vivo and in silico approaches can be integrated to strengthen basic patho-biological research, translational drug screening and clinical personalized therapies. We hope that this review will promote synergistic collaborations to accelerate progress of LN-mimicking systems to enhance understanding of immuno-complexity.

An amphiphilic dendrimer as a light-activable immunological adjuvant for in situ cancer vaccination.

Immunological adjuvants are essential for successful cancer vaccination. However, traditional adjuvants have some limitations, such as lack of controllability and induction of systemic toxicity, which restrict their broad application. Here, we present a light-activable immunological adjuvant (LIA), which is composed of a hypoxia-responsive amphiphilic dendrimer nanoparticle loaded with chlorin e6. Under irradiation with near-infrared light, the LIA not only induces tumour cell lysis and tumour antigen release, but also promotes the structural transformation of 2-nitroimidazole containing dendrimer to 2-aminoimidazole containing dendrimer which can activate dendritic cells via the Toll-like receptor 7-mediated signaling pathway. The LIA efficiently inhibits both primary and abscopal tumour growth and induces strong antigen-specific immune memory effect to prevent tumour metastasis and recurrence in vivo. Furthermore, LIA localizes the immunological adjuvant effect at the tumour site. We demonstrate this light-activable immunological adjuvant offers a safe and potent platform for in situ cancer vaccination.

Effects of Dietary Energy Level on Performance, Plasma Parameters, and Central AMPK Levels in Stressed Broilers.

This study aimed to characterize the effects of diets with different energy levels on the growth performance, plasma parameters, and central AMPK signaling pathway in broilers under dexamethasone (DEX)-induced stress. A total of 216 1-day-old male broiler chickens were allocated to groups fed with high (HED), National Research Council-recommended (control), or low (LED) energy diets. At 10 days old, chickens were treated with or without dexamethasone (DEX, 2 mg/kg body weight) for 3 consecutive days. HED increased broiler average daily gain (ADG) at 10 days old, compared with the LED (P < 0.05), while average daily feed intake (ADFI) and feed conversion rate (FCR) decreased as the dietary energy level increased (P < 0.05). Chickens fed a HED had higher total protein (TP) content, albumin (ALB), glucose (GLU), total cholesterol (TCHO), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol, compared with the control group (P < 0.05). At 13 days old, DEX decreased ADG and increased FCR in broilers fed with different energy diets (P < 0.05). The DEX-HED group had a higher ADFI than non-DEX treated HED group chickens. In addition, TP, ALB, triglycerides (TG), TCHO, HDL, and LDL content levels in the DEX group were higher than those in the control group (P < 0.05). The uric acid (UA) content of the LED group was higher than that of the HED group (P < 0.05). Further, gene expression levels of liver kinase B1, AMP-activated protein kinase α1, neuropeptide Y, and GC receptor in the hypothalamus were increased in chickens treated with DEX (P < 0.05). There was a trend toward interaction between plasma TCHO and hypothalamic LKB1 expression (0.05 < P < 0.1). In conclusion, this study suggests that HED improves growth performance, plasma glucose and total cholesterol at 10 days old broilers, but had no significant effect on performance, plasma parameters, and central AMPK in stressed broilers.

Effect of dexamethasone on gene expression of cannabinoid receptor type 1 and adenosine monophosphate-activated protein kinase in the hypothalamus of broilers (Gallus domesticus).

Hypothalamic neural circuits play a critical role in integrating peripheral signals and conveying information about energy and nutrient status. We detected cannabinoid receptor type 1 (CB1) distribution in the hypothalamus, liver, duodenum, jejunum, and ileum among 7- and 35-day-old broilers. The effects of dexamethasone (DEX) on CB1 gene expression were evaluated by in vitro and in vivo experiments on glucocorticoid receptor (GR) and adenosine monophosphate-activated protein kinase (AMPK) in the hypothalamus of broilers. In vitro, hypothalamic cells from 17-day-old broiler embryos were incubated with either 0.1% dimethyl sulfoxide or DEX (100 nmol/mL) for 1 h. In the in vivo study, 28-day-old broilers were injected with DEX for 24 h or 72 h. Results showed that CB1 was mainly expressed in the hypothalamus, and 72 h DEX treatment increased the expression. One-day treatment of broilers with DEX did not change the hypothalamic CB1 gene expression. Moreover, DEX treatment for 24 h and 72 h increased the mRNA level of hypothalamic AMPKα2 and GR. However, no differences were observed on the gene expression of CB1, GR, and AMPKα2 in hypothalamic cells with DEX-treated for 1 h. In conclusion, CB1 is mainly expressed in the hypothalamus of broilers; 72-h DEX exposure can regulate the CB1 system and AMPK signaling pathway of the broiler hypothalamus.

Proton-driven transformable nanovaccine for cancer immunotherapy.

Cancer vaccines hold great promise for improved cancer treatment. However, endosomal trapping and low immunogenicity of tumour antigens usually limit the efficiency of vaccination strategies. Here, we present a proton-driven nanotransformer-based vaccine, comprising a polymer-peptide conjugate-based nanotransformer and loaded antigenic peptide. The nanotransformer-based vaccine induces a strong immune response without substantial systemic toxicity. In the acidic endosomal environment, the nanotransformer-based vaccine undergoes a dramatic morphological change from nanospheres (about 100 nanometres in diameter) into nanosheets (several micrometres in length or width), which mechanically disrupts the endosomal membrane and directly delivers the antigenic peptide into the cytoplasm. The re-assembled nanosheets also boost tumour immunity via activation of specific inflammation pathways. The nanotransformer-based vaccine effectively inhibits tumour growth in the B16F10-OVA and human papilloma virus-E6/E7 tumour models in mice. Moreover, combining the nanotransformer-based vaccine with anti-PD-L1 antibodies results in over 83 days of survival and in about half of the mice produces complete tumour regression in the B16F10 model. This proton-driven transformable nanovaccine offers a robust and safe strategy for cancer immunotherapy.

Effects of dietary energy level on appetite and central adenosine monophosphate-activated protein kinase (AMPK) in broilers.

Adenosine monophosphate-activated protein kinase (AMPK) acts as a sensor of cellular energy changes and is involved in the control of food intake. A total of 216 1-d-old broilers were randomly allotted into 3 treatments with 6 replicates per treatment and 12 broilers in each cage. The dietary treatments included 1) high-energy (HE) diet (3,500 kcal/kg), 2) normal-energy (NE) diet (3,200 kcal/kg), and 3) low-energy (LE) diet (2,900 kcal/kg). The present study was conducted to investigate the effects of dietary energy level on appetite and the central AMPK signal pathway. The results showed that a HE diet increased average daily gain (ADG), whereas a LE diet had the opposite effect (P < 0.05, N = 6). The average daily feed intake (ADFI) of the chickens fed the LE diet was significantly higher than that of the control (P < 0.05, N = 6). Overall, the feed conversion rate gradually decreased with increasing dietary energy level (P < 0.05, N = 6). Moreover, the chickens fed the LE and HE diets demonstrated markedly improved urea content compared with the control group (P < 0.0001, N = 8). The triglyceride (TG) content in the LE group was obviously higher than that in the HE group but showed no change compared with the control (P = 0.0678, N = 8). The abdominal fat rate gradually increased with increased dietary energy level (P = 0.0927, N = 8). The HE group showed downregulated gene expression levels of liver kinase B1 (LKB1), neuropeptide Y (NPY), cholecystokinin (CCK), and glucocorticoid receptor (GR) in the hypothalamus compared with the control group (P < 0.05, N = 8). However, LE treatment significantly increased the mRNA level of AMP-activated protein kinase α2 (AMPKα2) compared with other groups (P = 0.0110, N = 8). In conclusion, a HE diet inhibited appetite and central AMPK signaling. In contrast, a LE diet activated central AMPK and appetite. Overall, the central AMPK signal pathway and appetite were modulated in accordance with the energy level in the diet to regulate nutritional status and maintain energy homeostasis in birds.

Thermo-responsive triple-function nanotransporter for efficient chemo-photothermal therapy of multidrug-resistant bacterial infection.

New strategies with high antimicrobial efficacy against multidrug-resistant bacteria are urgently desired. Herein, we describe a smart triple-functional nanostructure, namely TRIDENT (Thermo-Responsive-Inspired Drug-Delivery Nano-Transporter), for reliable bacterial eradication. The robust antibacterial effectiveness is attributed to the integrated fluorescence monitoring and synergistic chemo-photothermal killing. We notice that temperature rises generated by near-infrared irradiation did not only melt the nanotransporter via a phase change mechanism, but also irreversibly damaged bacterial membranes to facilitate imipenem permeation, thus interfering with cell wall biosynthesis and eventually leading to rapid bacterial death. Both in vitro and in vivo evidence demonstrate that even low doses of imipenem-encapsulated TRIDENT could eradicate clinical methicillin-resistant Staphylococcus aureus, whereas imipenem alone had limited effect. Due to rapid recovery of infected sites and good biosafety we envision a universal antimicrobial platform to fight against multidrug-resistant or extremely drug-resistant bacteria.

A non-conjugated polyethylenimine copolymer-based unorthodox nanoprobe for bioimaging and related mechanism exploration.

Unconventional non-conjugated photoluminescent polymers have attracted increasing attention in bioimaging application, however their nonclassical photoluminescence mechanisms remain largely unclear. Herein, an amphiphilic copolymer polyethyleneimine-poly(d,l-lactide) (PEI-PDLLA) was synthesized and the obtained PEI-PDLLA copolymer exhibited intrinsic visible blue luminescence in the solid and concentrated solution states under 365 nm UV light irradiation. Using a computational assay approach, we investigated the unconventional photoluminescence mechanism of PEI-PDLLA. The results revealed that such photoluminescence should be related to the "clustered heteroatom chromophores" formed by through-space electronic interactions of N-heteroatoms in PEI. The copolymers can function as a fluorescent nanoprobe (PEI-PDLLA NPs) via a facile nanoprecipitation method and the self-assembly mechanism of PEI-PDLLA NPs was also investigated in-depth by molecular dynamics simulation. Intriguingly, the PEI-PDLLA NPs exhibited a remarkable excitation-dependent multi-wavelength emission characteristic, which was promising in acquiring a high precision imaging effect. Moreover, in contrast with conventional organic dyes with aggregation-caused quenching (ACQ), the fluorescence intensity of the PEI-PDLLA NPs was enhanced with increasing solution concentration. Furthermore, their applications in bioimaging indicated that PEI-PDLLA NPs could be utilized as a lysosome-specific and tumor-targeted nanoprobe with excellent photostability and good biocompatibility.

Effects of glucocorticoids on lipid metabolism and AMPK in broiler chickens' liver.

Adenosine monophosphate-activated protein kinase (AMPK) plays a pivotal role in the regulation of carbohydrate, lipid, and protein metabolism in animals. In this study, we examined whether any cross talk exists between glucocorticoids and AMPK in the regulation of the liver bile acid biosynthesis pathway. Dexamethasone treatment decreased the growth performance of broiler chickens. The liver mRNA levels of fatty acid transport protein (FATP-1), farnesoid X receptor (FXR), AMPK alpha 1 subunit (AMPKα1), and glucocorticoid receptor were significantly upregulated in DEX-treated broilers; the gene expression of liver cholesterol 7 alpha-hydroxylase (CYP7A1) was significantly downregulated. The protein level of liver CYP7A1 was significantly decreased by DEX treatment at both 24 and 72 h, while the protein level of p-AMPK/ t-AMPK stayed unchanged. In the in vitro cultured hepatocytes, compound C pretreatment blocked the increase in CYP7A1 protein level by DEX and significantly suppressed FATP-1, SREBP-1c, FXR, and CYP7A1 gene expression stimulated by DEX. Compound C treatment significantly reduces the protein level of p-AMPK, and the combination of compound C and DEX significantly reduces the protein level of t-AMPK. Thus, glucocorticoids affected liver AMPK and the bile acid synthesis signal pathway, and AMPK might be involved in the glucocorticoid effect of liver bile acid synthesis.

From one to all: self-assembled theranostic nanoparticles for tumor-targeted imaging and programmed photoactive therapy.

BACKGROUND: In recent years, multifunctional theranostic nanoparticles have been fabricated by integrating imaging and therapeutic moieties into one single nano-formulations. However, Complexity of production and safety issues limits their further application. RESULTS: Herein, we demonstrated self-assembled nanoparticles with single structure as a "from one to all" theranostic platform for tumor-targeted dual-modal imaging and programmed photoactive therapy (PPAT). The nanoparticles were successfully developed through self-assembling of hyaluronic acid (HA)-cystamine-cholesterol (HSC) conjugate, in which IR780 was simultaneously incorporated (HSCI NPs). Due to the proper hydrodynamic size and intrinsic targeting ability of HA, the HSCI NPs could accumulate at the tumor site effectively after systemic administration. In the presence of incorporated IR780, in vivo biodistribution and accumulation behaviors of HSCI NPs could be monitored by photoacoustic imaging. After cellular uptake, the HSCI NPs would disintegrate resulting from cystamine reacting with over-expressed GSH. The released IR780 would induce fluorescence "turn-on" conversion, which could be used to image tumor sites effectively. Upon treatment with 808 nm laser irradiation, PPAT could be achieved in which generated reactive oxygen species (ROS) would produce photodynamic therapy (PDT), and subsequently the raised temperature would be beneficial to tumor photothermal therapy (PTT). CONCLUSION: The self-assembled HSCI NPs could act as "from one to all" theranostic platform for high treatment efficiency via PPAT pattern, which could also real-time monitor NPs accumulation by targeted and dual-modal imaging in a non-invasive way.

Auto-fluorescent polymer nanotheranostics for self-monitoring of cancer therapy via triple-collaborative strategy.

Aberrant regulation of angiogenesis supply sufficient oxygen and nutrients to exacerbate tumor progression and metastasis. Taking this hallmark of cancer into account, reported here is a self-monitoring and triple-collaborative therapy system by auto-fluorescent polymer nanotheranostics which could be concurrently against angiogenesis and tumor cell growth by combining the benefits of anti-angiogenesis, RNA interfere and photothermal therapy (PTT). Auto-fluorescent amphiphilic polymer polyethyleneimine-polylactide (PEI-PLA) with positive charge can simultaneously load hydrophobic antiangiogenesis agent combretastatin A4 (CA4), NIR dye IR825 and absorb negatively charged heat shock protein 70 (HSP70) inhibitor (siRNA against HSP70) to construct self-monitoring nanotheranostics (NPICS). NPICS can effectively restrain the expression of HSP70 to reduce their endurance to the IR825-mediated PTT, leading to an enhanced photocytotoxicity. In a xenograft mouse tumor model, NPICS show an effect of inhibition of tumor angiogenesis and also display a highly synergistic anticancer efficacy with NIR laser irradiation. Significantly, based on its inherent auto-fluorescence, PEI-PLA not only serves as the drug carrier, but also as the self-monitor to real-time track NPICS biodistribution and tumor accumulation via fluorescence imaging. Moreover, IR825 endows NPICS could also be used as photoacoustic (PA) agents for in vivo PA imaging. This nanoplatform shows enormous potentials in cancer theranostics.

Core-Satellite Nanomedicines for in Vivo Real-Time Monitoring of Enzyme-Activatable Drug Release by Fluorescence and Photoacoustic Dual-Modal Imaging.

It remains an unresolved challenge to achieve spatial and temporal monitoring of drug release from nanomedicines (NMs) in vivo, which is of crucial importance in disease treatment. To tackle this issue, we constructed core-satellite ICG/DOX@Gel-CuS NMs, which consist of gelatin (Gel) nanoparticles (NPs) with payloads of near-infrared fluorochrome indocyanine green (ICG) and chemo-drug doxorubicin (DOX) and surrounding CuS NPs. The fluorescence of ICG was initially shielded by satellite CuS NPs within the intact ICG/DOX@Gel-CuS NMs and increased in proportion to the amount of DOX released from NMs in response to enzyme-activated NMs degradation. For more comprehensive understanding of the drug-release profile, a theoretical model derived from computer simulation was employed to reconstruct the enzyme-activatable drug release of the ICG/DOX@Gel-CuS NMs, which demonstrated the underlying kinetics functional relationship between the released DOX amount and recovered ICG fluorescence intensity. The kinetics of drug release in vivo was assessed by administrating ICG/DOX@Gel-CuS NMs both locally and systemically into MDA-MB-231 tumor-bearing mice. Upon accumulation of ICG/DOX@Gel-CuS NMs in the tumor, overexpressed enzymes triggered the degradation of the gelatin scaffold as well as the release of DOX and ICG, which can be visually depicted with the ICG fluorescence signal increasing only in the tumor area by fluorescence imaging. Additionally, the photoacoustic signal from CuS NPs was independent from the physical status of ICG/DOX@Gel-CuS NMs and hence was utilized for real-time NMs tracking. Thus, by taking advantage of the core-satellite architecture and NMs degradability in tumor site, the DOX release profile of ICG/DOX@Gel-CuS NMs was monitored by fluorescence and photoacoustic dual-modal imaging in a real-time noninvasive manner.

Biocompatible semiconducting polymer nanoparticles as robust photoacoustic and photothermal agents revealing the effects of chemical structure on high photothermal conversion efficiency.

Understanding the relationship between polymer chemical structure and its performance of photoacoustic imaging (PAI) and photothermal therapy (PTT) is important for developing ideal PAI/PTT agents. In this report, four semiconducting polymer nanoparticles (SPNs) with different donor-acceptor architectures are self-assembled for highly effective PAI-guided PTT. In particular, SPN1 with the longest π-conjugation length and the highest mass extinction coefficient which are beneficial for intramolecular charge transfer as well as light harvesting, exhibits the highest photothermal conversion efficiency up to 52.6%. Moreover, the as-prepared SPN1 possess good water-dispersibility, robust size-stability and excellent photothermal properties. Furthermore, the SPN1 not only exhibits a remarkable cancer cell-killing ability but also shows a prominent tumor inhibition capacity. Finally, the as-prepared water-dispersible SPN1 displays good biocompatibility and biosafety, making it a promising candidate for future biomedical applications. Considering the plenty of near-infrared absorbing semiconducting polymer available, our work provides fundamental insights for rational design and preparation of highly efficient SPN-based PAI/PTT agents for cancer theranostics.