Stem cell-derived exosomes for chronic wound repair.

Stem cells possess the capability of self-renewal and multipotency, which endows them with great application potential in wound repair fields. Yet, several problems including immune concerns, ethical debates, and oncogenicity impede the broad and deep advance of stem cell-based products. Recently, owing to their abundant resources, excellent biocompatibility, and ease of being engineered, stem cell-derived exosomes were proved to be promising nanomedicine for curing chronic wounds. What is more, stem cell-derived exosomes are almost the mini record of their maternal cells, which even equipped them with the unique characteristics of stem cells. Chronic wound healing efficacy is dominated by several complicated factors, especially the excessive inflammation conditions and impaired vessels. Therefore, this review tries to concentrate on the current advances of stem cell-derived exosomes for reducing inflammation and promoting angiogenesis in chronic wound healing processes. Last but not least, the existing limitations and future perspectives of stem cell-derived exosomes for chronic wound treatment are also outlined.

Block catiomers with flanking hydrolyzable tyrosinate groups enhance in vivo mRNA delivery via π-π stacking-assisted micellar assembly.

Messenger RNA (mRNA) therapeutics have recently demonstrated high clinical potential with the accelerated approval of SARS-CoV-2 vaccines. To fulfill the promise of unprecedented mRNA-based treatments, the development of safe and efficient carriers is still necessary to achieve effective delivery of mRNA. Herein, we prepared mRNA-loaded nanocarriers for enhanced in vivo delivery using biocompatible block copolymers having functional amino acid moieties for tunable interaction with mRNA. The block copolymers were based on flexible poly(ethylene glycol)-poly(glycerol) (PEG-PG) modified with glycine (Gly), leucine (Leu) or tyrosine (Tyr) via ester bonds to generate block catiomers. Moreover, the amino acids can be gradually detached from the block copolymers after ester bond hydrolyzation, avoiding cytotoxic effects. When mixed with mRNA, the block catiomers formed narrowly distributed polymeric micelles with high stability and enhanced delivery efficiency. Particularly, the micelles based on tyrosine-modified PEG-PG (PEG-PGTyr), which formed a polyion complex (PIC) and π-π stacking with mRNA, displayed excellent stability against polyanions and promoted mRNA integrity in serum. PEG-PGTyr-based micelles also increased the cellular uptake and the endosomal escape, promoting high protein expression both in vitro and in vivo. Furthermore, the PEG-PGTyr-based micelles significantly extended the half-life of the loaded mRNA after intravenous injection. Our results highlight the potential of PEG-PGTyr-based micelles as safe and effective carriers for mRNA, expediting the rational design of polymeric materials for enhanced mRNA delivery.

Phenotypic and genotypic characteristics of Acinetobacter baumannii enrolled in the relationship among antibiotic resistance, biofilm formation and motility.

Acinetobacter baumannii is an important pathogen in clinical. The factors of biofilm formation, antibiotic resistance and motility contribute great to A. baumannii in persisting in stressed environment, and further leads to nosocomial infections. 70 A. baumannii clinical isolates were investigated for their clinical characteristics of infection. Among the tested strains, 54 (77.1%) isolates were obtained from ICUs, with the frequency of multidrug-resistance (MDR) at 55.7%, and that of extensively drug-resistance (XDR) at 31.4%. 97.1% of the clinical isolates could form biofilms, in which 4.3% possessed weak biofilm formation ability, while 41.4% and 51.4% were moderate and strong biofilm producers, respectively. A strong correlation between antibiotic resistance and biofilm formation ability was found that all the resistant strains could form biofilms, with the majority in moderate and strong levels, but 2.9% sensitive isolates had no such ability. However, the sensitive strains that could produce biofilms showed stronger biofilm formation capacity in the early stage before 24 h compared to the resistant isolates, though they became weaker afterwards. 24 biofilm-related genes and two blaOXA genes were found in both biofilm-forming and non-biofilm-forming strains, but with higher prevalence in the strains that could produce biofilms. No correlation was detected between twitching motility with antibiotic susceptibility or biofilm formation. These results raised a viewpoint that examining timepoint is a key factor for determining the biofilm formation ability, and further highlighted the importance of the appropriate surveillance and control measures in preventing the emergence and transmission of MDR and XDR A. baumannii.

Multistimuli Responsive Core-Shell Nanoplatform Constructed from Fe3 O4 @MOF Equipped with Pillar[6]arene Nanovalves.

An intelligent theranostic nanoplatform based on nanovalve operated metal-organic framework (MOF) core-shell hybrids, incorporating tumorous microenvironment-triggered drug release, magnetic resonance imaging (MRI) guidance, sustained release, and effective chemotherapy in one pot is reported. The core-shell hybrids are constructed by an in situ growth method, in which Fe3 O4 particles with superior abilities of MRI and magnetic separation form the core and UiO-66 MOF with high loading capacity compose the shell, and then are surface-installed with pillararene-based pseudorotaxanes as tightness-adjustable nanovalves. This strategy endows the system with the ability of targeted, multistimuli responsive drug release in response to pH changes, temperature variations, and competitive agents. Water-soluble carboxylatopillar[6]arene system achieved sustained drug release over 7 days due to stronger host-guest binding, suggesting that the nanovalve tightness further reinforces the desirable release of anticancer agent over a prolonged time at the lesion site.

[Research progress of Tibetan medicine "Zha-xun"].

Zha-xun is widely used in Tibetan medicine and is also an international traditional medicine. This article would summarize the use status and research progress of Zha-xun by various ethnic groups all over the world, and the results show that it has various synonyms but most of them imply its most characteristic feature-outflow from the rock; Zha-xun resources are distributed in various places of the world, and its bearing spots are closely related to the geological structure; there are sharp arguments on the origins of Zha-xun, mainly including the minerals origin, biological fossils origin, biological origin, etc. Zha-xun has multiple functions and is mainly used to treat stomach disease, liver disease and rheumatoid arthritis in China, and premature ejaculation, impotence, vaginitis embolism in foreign countries. "Iron" Zha-xun is used into medicines both at home and abroad. According to ancient materia medica texts, it was mainly classified into five types, including gold Zha-xun, silver Zha-xun, copper Zha-xun, iron Zha-xun and lead Zha-xun mainly based on the predominance of color rather than the minerals contained. It is commonly believed by the domestic and foreign scholars that humic acid is the main medicinal part of Zha-xun, and their studies have found that it has a variety of pharmacological activities such as anti-ulcer, anti-inflammatory, liver protection, analgesia, immune regulation, increasing sexual desire and fertility, antioxidation, antibacterial, antidiabetic, antiepileptic, antipsychotic, etc. This paper provides a scientific basis for the rational utilization of Zha-xun resources.

[Classics textual research and using situation investigation of Tibetan medicine "Zha-xun"].

In this article the classics textual research to the origin of "Zha-xun" was carried out, the ethnobotanical research methods, the origin of visits, key informant interviews, sample collection and textual research were applied in the research. The results showed that the hypothesis of Zha-xun"s origin mainly included "source of mine", "source of feces", "source of monkey menstrual blood" in China. There were "source of fossil", "source of the plant secretion" abroad. The authors had interviewed the villagers at origin, herbalists, Tibetan doctors, herb dealers, foreign scholars for a total of 18 people, and collecting 45 batches medicinal materials. According to ancient Tibetan classics textual and Tibetan medicine doctors' views, medicinal materials were divided into the genuine and the substitutes. The genuine was identified as ancient so-called "iron" type "Zha-xun", and the substitute was fecal pellet bonding briquette. According to the field survey and literature research, "source of fossil" more in line with substance of Zha-xun was derived from the rock. As the results, the author believed that Zha-xun was the mixture of organic fossils from the rock seepage with flying squirrel, pika feces. So it is needed to be set up Zha-xun classification standard to evaluate the quality of medicinal materials. Meanwhile, it was necessary to further clarify fecal pellet substitute rationality. Above all, this article clarified the status of the use of Tibetan medicine-"Zha-xun", and laid the foundation of species systematics and quality standards research of "Zha-xun".

Polyion complex vesicles for photoinduced intracellular delivery of amphiphilic photosensitizer.

Polymer vesicles formed by a pair of oppositely charged poly(ethylene glycol) (PEG)-based block aniomer and homocatiomer, termed "PICsomes", have tunable size, and are characterized by unique semipermeable property due to the flexible and tunable hydrophilicity of polyion complex (PIC) membranes. The PICsomes can encapsulate a variety of molecules in an inner aqueous phase just by a simple vortex mixing of solution, expecting their utility as nanocontainers of substances with biomedical interests. Here, we report on a new functionality of the PICsomes: photoinduced release of photoactive agents for intracellular drug delivery. A potent photosensitizer, Al(III) phthalocyanine chloride disulfonic acid (AlPcS2a), was efficiently incorporated into the PICsomes (11%(w/w)), and its quick release was induced by photoirradiation possibly due to the photochemical damage of the PIC membranes. The combination of a high-resolution fluorescent confocal microscopy and a lysosome membrane-specific staining method revealed that such photoinduced release of AlPcS2a occurred even in the lysosomes of living cells after endocytic internalization. Simultaneously, the released AlPcS2a photochemically affected the integrity of the lysosomal membranes, leading to the translocation of AlPcS2a and PICsomes themselves to the cytoplasm. Consequently, the AlPcS2a-encapsulated PICsomes (AlPcS2a-PICsomes) exhibited appreciably stronger photocytotoxicity compared with free AlPcS2a alone. Thus, the AlPcS2a-PICsomes have promising feasibility for the photodynamic therapy or the photoinduced cytoplasmic delivery of therapeutic molecules.

Nanocarriers address intracellular barriers for efficient drug delivery, overcoming drug resistance, subcellular targeting and controlled release.

The cellular barriers are major bottlenecks for bioactive compounds entering into cells to accomplish their biological functions, which limits their biomedical applications. Nanocarriers have demonstrated high potential and benefits for encapsulating bioactive compounds and efficiently delivering them into target cells by overcoming a cascade of intracellular barriers to achieve desirable therapeutic and diagnostic effects. In this review, we introduce the cellular barriers ahead of drug delivery and nanocarriers, as well as summarize recent advances and strategies of nanocarriers for increasing internalization with cells, promoting intracellular trafficking, overcoming drug resistance, targeting subcellular locations and controlled drug release. Lastly, the future perspectives of nanocarriers for intracellular drug delivery are discussed, which mainly focus on potential challenges and future directions. Our review presents an overview of intracellular drug delivery by nanocarriers, which may encourage the future development of nanocarriers for efficient and precision drug delivery into a wide range of cells and subcellular targets.

Uncovering the Over-Smoothing Challenge in Image Super-Resolution: Entropy-Based Quantification and Contrastive Optimization.

PSNR-oriented models are a critical class of super-resolution models with applications across various fields. However, these models tend to generate over-smoothed images, a problem that has been analyzed previously from the perspectives of models or loss functions, but without taking into account the impact of data properties. In this paper, we present a novel phenomenon that we term the center-oriented optimization (COO) problem, where a model's output converges towards the center point of similar high-resolution images, rather than towards the ground truth. We demonstrate that the strength of this problem is related to the uncertainty of data, which we quantify using entropy. We prove that as the entropy of high-resolution images increases, their center point will move further away from the clean image distribution, and the model will generate over-smoothed images. Implicitly optimizing the COO problem, perceptual-driven approaches such as perceptual loss, model structure optimization, or GAN-based methods can be viewed. We propose an explicit solution to the COO problem, called Detail Enhanced Contrastive Loss (DECLoss). DECLoss utilizes the clustering property of contrastive learning to directly reduce the variance of the potential high-resolution distribution and thereby decrease the entropy. We evaluate DECLoss on multiple super-resolution benchmarks and demonstrate that it improves the perceptual quality of PSNR-oriented models. Moreover, when applied to GAN-based methods, such as RaGAN, DECLoss helps to achieve state-of-the-art performance, such as 0.093 LPIPS with 24.51 PSNR on 4× downsampled Urban100, validating the effectiveness and generalization of our approach.

The role of type VI secretion system genes in antibiotic resistance and virulence in Acinetobacter baumannii clinical isolates.

Introduction: The type VI secretion system (T6SS) is a crucial virulence factor in the nosocomial pathogen Acinetobacter baumannii. However, its association with drug resistance is less well known. Notably, the roles that different T6SS components play in the process of antimicrobial resistance, as well as in virulence, have not been systematically revealed. Methods: The importance of three representative T6SS core genes involved in the drug resistance and virulence of A. baumannii, namely, tssB, tssD (hcp), and tssM was elucidated. Results: A higher ratio of the three core genes was detected in drug-resistant strains than in susceptible strains among our 114 A. baumannii clinical isolates. Upon deletion of tssB in AB795639, increased antimicrobial resistance to cefuroxime and ceftriaxone was observed, alongside reduced resistance to gentamicin. The ΔtssD mutant showed decreased resistance to ciprofloxacin, norfloxacin, ofloxacin, tetracycline, and doxycycline, but increased resistance to tobramycin and streptomycin. The tssM-lacking mutant showed an increased sensitivity to ofloxacin, polymyxin B, and furazolidone. In addition, a significant reduction in biofilm formation was observed only with the ΔtssM mutant. Moreover, the ΔtssM strain, followed by the ΔtssD mutant, showed decreased survival in human serum, with attenuated competition with Escherichia coli and impaired lethality in Galleria mellonella. Discussion: The above results suggest that T6SS plays an important role, participating in the antibiotic resistance of A. baumannii, especially in terms of intrinsic resistance. Meanwhile, tssM and tssD contribute to bacterial virulence to a greater degree, with tssM being associated with greater importance.

Mesenchymal Stem Cell Derived Extracellular Vesicles: Promising Nanomedicine for Cutaneous Wound Treatment.

A skin wound represents a rupture caused by external damage or the existence of underlying pathological conditions. Sometimes, skin wound healing processes may place a heavy burden on patients, families, and society. Wound healing processes mainly consist of several continuous, dynamic, but overlapping stages, namely, the coagulation stage, inflammation stage, proliferation stage, and remodeling stage. Bacterial infection, excessive inflammation, impaired angiogenesis, and scar formation constitute the four significant factors impeding the recovery efficacy of skin wounds. This encourages scientists to develop multifunctional nanomedicines to meet challenging needs. As we know, mesenchymal stem cells (MSCs) have been widely explored for wound repair owing to their unique capability for self-renewal and multipotency. However, problems including immune concerns and legal restrictions should be properly resolved before MSC-based therapeutics are safely and widely used in clinics. Besides, maintaining the high viability/proliferation capability of MSCs during administration processes and therapy procedures is also one of the biggest technical bottlenecks. Extracellular vesicles (EVs) are cell-derived nanovesicles, that not only possess the basic characteristics and functions of their corresponding maternal cells but also contain several outstanding advantages including abundant sources, excellent biocompatibility, and convenient administration routes. Furthermore, the membrane surface and cavity are easy to flexibly modify to meet versatile application needs. Recently, MSC-derived EVs have emerged as promising therapeutics for skin wound repair. However, current reviews are too broad and rarely focused on the specific roles of EVs in the different stages of wound recovery. Therefore, it is quite necessary to demonstrate the significance of stem cell-derived EVs in promoting wound healing from several specific aspects. Here, this review primarily tries to provide critical comments on current advances in EVs derived from MSCs for wound repair, particularly elaborating on their impressive roles in effectively eliminating infections, inhibiting inflammation, promoting angiogenesis, and reducing scar formation. Last but not least, current limitations and future prospects of EVs derived from MSCs in the areas of wound repair are also objectively analyzed.

Evolution of Toughening Mechanisms in PH13-8Mo Stainless Steel during Aging Treatment.

PH13-8Mo stainless steel has been widely used in aerospace, petroleum and marine construction, obtaining continuous investigation attention in recent years. Based on the response of a hierarchical martensite matrix and possible reversed austenite, a systematic investigation of the evolution of the toughening mechanisms in PH13-8Mo stainless steel as a function of aging temperature was carried out. It showed there was a desirable combination of high yield strength (~1.3 GPa) and V-notched impact toughness (~220 J) after aging between 540 and 550 °C. With the increase of aging temperature, the martensite matrix was recovered in terms of the refined sub-grains and higher ratio of high-angle grain boundaries (HAGBs). It should be noted there was a reversion of martensite to form austenite films subjected to aging above 540 °C; meanwhile, the NiAl precipitates maintained a well-coherent orientation with the matrix. Based on the post mortem analysis, there were three stages of the changing main toughening mechanisms: Stage I: low-temperature aging at around 510 °C, where the HAGBs contributed to the toughness by retarding the advance of cracks; Stage II: intermediate-temperature aging at around 540 °C, where the recovered laths embedded by soft austenite facilitated the improvement of toughness by synergistically increasing the advance path and blunting the crack tips; and Stage III: without the coarsening of NiAl precipitates around 560 °C, more inter-lath reversed austenite led to the optimum toughness, relying on "soft barrier" and transformation-induced plasticity (TRIP) effects.

Identifying TOPK and Hypoxia Hallmarks in Esophageal Tumors for Photodynamic/Chemo/Immunotherapy and Liver Metastasis Inhibition with Nanocarriers.

Although esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, there are major bottlenecks in its therapeutic approaches, primarily the identification of clinically relevant targets and the lack of effective targeted therapeutics. Herein, we identified the hallmarks of ESCC, namely, high T-lymphokine-activated killer cell-originated protein kinase (TOPK) expression in human ESCC tumors and its correlation with poor patient prognosis and hypoxia in the tumor microenvironment. We developed hypoxia-sensitive nanoparticles encapsulating TOPK inhibitor OTS964 and photosensitizer chlorin e6 for the imaging-directed precision therapy of ESCC tumors. The sub-100 nm monodisperse nanoparticles efficiently delivered drugs into the human ESCC KYSE 150 cancer cells to kill the cells. The nanoparticles were selectively accumulated in the ESCC tumors after intravenous (i.v.) injection, thereby enabling the diagnosis and photoacoustic imaging-guided local laser irradiation of tumors. The combination of chemotherapy and photodynamic therapy effectively eradicated human ESCC KYSE 150 tumors and inhibited liver metastasis and recurrence by suppressing TOPK and inducing ESCC cell apoptosis. The nanoparticle-based therapies further stimulated high rates of natural killer cells in ESCC tumors, thereby exhibiting the potential of immunotherapy. This study identified important therapeutic targets of ESCC tumors and delineated an effective nanocarrier-based approach for tumor microenvironment and molecular targeted therapy.

The optimized carbapenem inactivation method for objective and accurate detection of carbapenemase-producing Acinetobacter baumannii.

The modified carbapenem inactivation method (mCIM) recommended by the Clinical and Laboratory Standards Institute is not applicable for detecting carbapenemases in Acinetobacter baumannii. Four currently reported phenotypic detection methods, namely, the modified Hodge test, the mCIM, the adjusted mCIM, and the simplified carbapenem inactivation method (sCIM), did not perform well in our 90 clinical A. baumannii isolates. Thus, the minimal inhibitory concentrations (MICs) of carbapenems and the existence and expression of carbapenemase-encoding genes were detected to explain the results. According to the E-test, which was more accurate than the VITEK 2 system, 80.0 and 41.1% were resistant to imipenem (IPM) and meropenem (MEM), respectively, and 14.4 and 53.3% exhibited intermediate resistance, respectively. Five ß-lactamase genes were found, of which blaOXA-51-like, blaTEM, and blaOXA-23-like were detected more frequently in 85 non-susceptible strains. The expression of blaOXA-23-like was positively correlated with the MIC values of IPM and MEM. Therefore, an improved approach based on the mCIM, designated the optimized CIM (oCIM), was developed in this study to detect carbapenemases more accurately and reproducibly. The condition was improved by evaluating the factors of A. baumannii inoculum, incubation broth volume, and MEM disk incubation time. Obvious high sensitivity (92.94%) and specificity (100.00%) were obtained using the oCIM, which was cost-effective and reproducible in routine laboratory work.

An Outer Membrane Protein YiaD Contributes to Adaptive Resistance of Meropenem in Acinetobacter baumannii.

Acinetobacter baumannii is an important nosocomial pathogen that can develop various resistance mechanisms to many antibiotics. However, little is known about how it evolves from an antibiotic sensitive to a resistant phenotype. In this study, we investigated the transition of outer membrane proteins (OMPs) under antibiotic stress and identified YiaD as an OMP marker involved in the development of adaptive resistance to meropenem (MEM) in A. baumannii. Following stimulation of a carbapenem-sensitive strain AB5116 with sub-MIC of MEM, yiaD showed significantly decreased expression, and this decrease continued with prolonged stimulation for 8 h. The downregulation of yiaD was not only observed in clinically sensitive strains but also in 45 carbapenem-resistant isolates that produced the ß-lactamases TEM and OXA-23. However, the extent of the reduction of yiaD expression in resistant strains was less than that in sensitive strains. Lack of yiaD resulted in a 4-fold increase in the MIC of AB5116 to MEM. The same level of depressed susceptibility induced by yiaD deletion was observed in both a growth curve test and a survival rate assay. Moreover, the colony shape became enlarged and irregular after loss of yiaD, and the biofilm formation ability of A. baumannii was influenced by YiaD. These results suggest that YiaD could respond to the stimulus of MEM in A. baumannii with a downregulation trend that kept pace with the prolonged stimulation time, indicating that it participates in various routes to benefit MEM resistance evolution in both carbapenem-sensitive and -resistant A. baumannii strains. IMPORTANCE Acinetobacter baumannii can develop various resistance mechanisms to carbapenems. However, the factors involved in the evolutionary process that leads from transition to the sensitive to resistant phenotype are not clear. The outer membrane protein YiaD of A. baumannii was downregulated under the stress of meropenem (MEM), and its expression level was continuously reduced with prolonged stimulation time. The downregulation of yiaD was not only observed in sensitive strains but also in carbapenem-resistant isolates producing the ß-lactamases TEM and OXA-23. However, the extent of yiaD reduction was less in resistant strains than in sensitive strains. Lack of yiaD resulted in an increased MEM MIC, enlarged and irregular colonies, and decreased biofilm formation ability. These results suggest that YiaD responds to MEM stimulus in A. baumannii and participates in the adaptive resistance of MEM in both carbapenem-sensitive and -resistant strains.

Functional metal-organic framework-based nanocarriers for accurate magnetic resonance imaging and effective eradication of breast tumor and lung metastasis.

The use of nanoscale metal-organic frameworks (MOFs) as drug delivery vehicles has attracted considerable attention in tumor therapy. In this study, novel biocompatible MOF-based nanocarriers were used as part of a facile and reproducible strategy for precision cancer theranostics. Both diagnostic (Mn2+) and therapeutic compounds (doxorubicin, DOX) were incorporated into the multifunctional MOF-based nanocarriers, which exhibited high colloidal stability and promoted T1-weighted proton relaxivity and low-pH-activated drug release. The obtained MOF-based nanocarriers exhibited significantly high cellular uptake and efficient intracellular drug delivery into cancer cells, which resulted in high apoptosis and cytotoxicity, in addition to effectively inhibiting the migration of 4T1 breast cancer cells. Moreover, the MOF-based nanocarriers could intensively deliver diagnostic and therapeutic agents to tumors to enable precise visualization of the nanocarrier accumulation and accurate tumor positioning, diagnosis, and imaging-guided therapy using magnetic resonance imaging (MRI). In addition, the functional MOF-based nanocarriers exhibited effective ablation of the primary breast cancer, as well as significant inhibition of lung metastasis with a high survival rate. Therefore, the developed nanocarriers represent a viable platform for cancer theranostics.

Tumor hypoxia-activated combinatorial nanomedicine triggers systemic antitumor immunity to effectively eradicate advanced breast cancer.

Hypoxia is a major obstacle towards successful cancer treatment, due to the hypoxia-mediated resistance to radiotherapy and chemotherapy, as well as immunosuppression. Therefore, engineering hypoxia-sensitive cytotoxic and immunogenic nanomedicines would promote the therapeutic efficacy. In this study, we developed novel tumor-targeted polymeric micelles sensing hypoxia in tumors to activate strong cytotoxicity and immunogenic responses for effectively eradicating advanced breast cancer. The hypoxia-activatable polymeric micelles could efficiently deliver anticancer drugs and photosensitizers into cancer cells, to trigger synergistic cytotoxicity and immunogenic cell death through chemotherapy and photodynamic therapy (PDT)/photothermal therapy (PTT). The long-circulating micelles efficiently delivered drugs to triple negative 4T1 breast tumors for accurate tumor diagnosis by photoacoustic imaging (PA), and effectively eliminating primary tumors without recurrence, including hypoxic 4T1 tumors. In addition, the micelle-based eradication of primary tumors could elicit robust systemic immune responses to inhibit tumor recurrence and significantly suppress distant 4T1 tumors and lung metastasis by combining with CpG and aCTLA4. These results indicate the high performance of our innovative multifunctional micelles for synergistic therapy against tumor malignancy, bringing opportunity for effectively dealing with disseminated and metastatic tumors.

Nanoprobe-Based Magnetic Resonance Imaging of Hypoxia Predicts Responses to Radiotherapy, Immunotherapy, and Sensitizing Treatments in Pancreatic Tumors.

Accurate diagnosis of tumors and predicting the therapeutic responses are highly demanded in the clinic to improve the treatment efficacy and survival rates. Since hypoxia develops in the progression of tumors and inversely correlates with prognosis and promotes resistance to radiotherapies and immunotherapies, it is a potential marker for therapeutic prediction. Therefore, effective discrimination of tumor hypoxia for predicting therapeutic outcomes is critical. Here, a magnetic resonance imaging (MRI)-based diagnosis strategy using contrast-amplifying nanoprobes that sense tumor acidosis and real-time observation of hypoxic conditions in tumors has been developed, aiming at accurate detection of pancreatic tumors and prediction of therapeutic effects. Our approach selectively probed xenograft, allograft, and transgenic spontaneous models of intractable pancreatic cancer, which lacks standardized predictive markers to identify patients who benefit most from treatments, and effectively discriminated the intratumoral hypoxia levels. By stratification of pancreatic tumors based on quantitative MR imaging of hypoxia, it enabled prediction of the responses to radiotherapy and immune checkpoint inhibitors. Moreover, the nanoprobe-based MRI could monitor hypoxia reduction by tumor normalization treatments, which permits visualizing pancreatic tumors that will respond to immune checkpoint blockade therapy, enhancing the response rate. The results demonstrate the potential of our strategy for accurate tumor diagnosis, patient stratification, and effective therapy.

Stimuli-responsive nanocarriers for drug delivery, tumor imaging, therapy and theranostics.

In recent years, much progress has been motivated in stimuli-responsive nanocarriers, which could response to the intrinsic physicochemical and pathological factors in diseased regions to increase the specificity of drug delivery. Currently, numerous nanocarriers have been engineered with physicochemical changes in responding to external stimuli, such as ultrasound, thermal, light and magnetic field, as well as internal stimuli, including pH, redox potential, hypoxia and enzyme, etc. Nanocarriers could respond to stimuli in tumor microenvironments or inside cancer cells for on-demanded drug delivery and accumulation, controlled drug release, activation of bioactive compounds, probes and targeting ligands, as well as size, charge and conformation conversion, etc., leading to sensing and signaling, overcoming multidrug resistance, accurate diagnosis and precision therapy. This review has summarized the general strategies of developing stimuli-responsive nanocarriers and recent advances, presented their applications in drug delivery, tumor imaging, therapy and theranostics, illustrated the progress of clinical translation and made prospects.