Exosomal circRNAs in the plasma serve as novel biomarkers for IPF diagnosis and progression prediction.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a type of chronic interstitial pneumonia, often fatal, with elusive causes and a bleak prognosis. Its treatment options are limited and largely ineffective. Early detection and precise diagnosis are pivotal in managing the disease effectively and enhancing patient survival rates. Recently, the quest for trustworthy biomarkers for IPF has gained momentum. Notably, emerging studies indicate that circular RNAs (circRNAs) found in exosomes may hold significant potential as valuable diagnostic markers. METHODS: In this study, we initially explored the expression profile of circRNAs in exosomes sourced from the blood of IPF patients and healthy volunteers, employing a human circRNA microarray. We then utilized RT-qPCR to corroborate the dysregulated circRNAs identified by the microarray during the training phase. Next, the circRNAs that displayed a significant increase during the training phase were selected for further validation in a larger cohort encompassing 113 IPF patients and 76 healthy volunteers. Ultimately, the expression level and function of hsa_circ_0044226 were substantiated through a series of in vivo and in vitro experiments. RESULTS: Utilizing a human circRNA microarray, we identified 11 dysregulated circRNAs in the exosomes derived from the blood of IPF patients and control volunteers. Subsequent RT-qPCR analysis revealed significant increases in three circRNAs (hsa_circ_0044226, hsa_circ_0004099, hsa_circ_0008898) within the IPF patients. Notably, hsa_circ_0044226 was markedly elevated in patients experiencing acute exacerbation of IPF (AE-IPF) compared to those with stable IPF (S-IPF). Additionally, an upregulation of hsa_circ_0044226 was observed in the blood exosomes derived from a bleomycin-induced IPF mouse model. CONCLUSION: The expression levels of hsa_circ_0044226, hsa_circ_0004099, and hsa_circ_0008898 in plasma exosomes introduce a new paradigm of biomarkers for the diagnosis and progression of IPF.

Early predictor for differentiation syndrome in newly diagnosed acute promyelocytic leukaemia patients treated with single-agent arsenic trioxide.

Differentiation syndrome (DS) is the second leading cause of death in acute promyelocytic leukaemia (APL) patients. Few studies have tested predictors of DS events. This study aimed to identify optimized predictors of DS events related to APL. The data of 298 consecutive patients who were newly diagnosed with APL between December 2012 and June 2023 were retrospectively investigated. A systematic review of computer-based patient medical records was conducted to obtain clinical data, including baseline characteristics, routine blood examination findings, biochemical indices and clinical manifestations of DS. Among the 298 patients, 158 were classified into the no-DS group, while 140 had DS. Compared with those of patients without DS, the peripheral blast count, age, and WBC count at each time point were significantly different in patients with DS (P < 0.05 for all time points). Generalized linear mixed models (GLMMs) revealed that WBC Double (Coeff. 0.442, P = 0.000) and WBCPeak (Coeff. 0.879, P = 0.000) were independent risk factors for DS. The frequencies of clinical manifestations of unexplained fever (P = 0.003), dyspnoea (P = 0.002), weight gain of more than 5 kg (P = 0.006), pleural effusion (P = 0.001), pulmonary infiltrates (P < 0.001), pericardial effusion (P = 0.002) and renal failure (P = 0.006) were considerably lower in moderate DS patients than in severe DS patients. The WBCDouble occurs earlier than the WBCpeak occurrence, so WBC Double might be a new indicator of DS.

Associations between urbanization and the home language environment: Evidence from a LENA study in rural and peri-urban China.

In low- and middle-income countries, urbanization has spurred the expansion of peri-urban communities, or urban communities of formerly rural residents with low socioeconomic status. The growth of these communities offers researchers an opportunity to measure the associations between the level of urbanization and the home language environment (HLE) among otherwise similar populations. Data were collected in 2019 using Language Environment Analysis observational assessment technology from 158 peri-urban and rural households with Han Chinese children (92 males, 66 females) aged 18-24 months in China. Peri-urban children scored lower than rural children in measures of the HLE and language development. In both samples, child age, gender, maternal employment, and sibling number were positively correlated with the HLE, which was in turn correlated with language development.

Value of the FDP/FIB ratio in predicting early severe bleeding events in patients with newly diagnosed acute promyelocytic leukemia.

Severe bleeding is the leading cause of early death in patients with newly diagnosed acute promyelocytic leukemia (APL). However, there are no means for hemorrhagic risk stratification in APL. This study aimed to identify optimized predictors of severe bleeding events related to APL. A total of 109 consecutive patients with newly diagnosed APL from January 2015 to April 2022 were retrospectively investigated. A systematic review of computer-based patient medical records was conducted to obtain clinical date, including baseline characteristics, routine blood examination findings, coagulation and fibrinolysis indexes, and bleeding events. Among the 109 patients, 89 were classified into the no-severe bleeding group, while 20 had severe bleeding. Compared with the patients with no severe bleeding, the patients with severe bleeding had significantly higher circulating leukemic cell percentages, disseminated intravascular coagulation (DIC) scores, D-dimer (D-D) levels, and fibrin degradation product (FDP) levels. They also had lower fibrinogen (FIB) levels and a longer prothrombin time. Multivariate analysis revealed that the circulating leukemic cell percentage (OR = 1.040, CI = 1.008-1.072, P = 0.012), FIB level (OR = 0.101, CI = 0.011-0.896, P = 0.040), and FDP level (OR = 1.012, CI = 1.000-1.024, P = 0.047) were independent risk factors for severe bleeding. FDP/FIB, D-D/FIB, and seven meaningful indicators in the single-factor analysis were included in the receiver operating characteristic (ROC) curve analysis. The results showed that FDP/FIB was the best indicator for predicting severe bleeding related to newly diagnosed APL. The area under the ROC curve of FDP/FIB was 0.915, and the best cutoff value was 61.77, with 100% sensitivity and 74.2% specificity. Statistical analysis showed a higher incidence of severe bleeding and higher DIC scores when FDP/FIB was >61.77 in APL patients. FDP/FIB has obvious advantages in predicting the degree of bleeding associated with primary promyelocytic leukemia; the greater the FDP/FIB value, the more severe the bleeding. The risk of severe bleeding was the highest when FDP/FIB > 61.77.

Periostin-targeted SDSSD peptide decorated calcium phosphate nanocomposites incorporation with simvastatin for osteoporosis treatment.

The limited options of anabolic drugs restrict their application potential in osteoporosis treatment, despite their theoretical superiority in therapeutic efficacy over antiresorptive drugs. As a prevailing strategy, nano-delivery systems could offer a wider choice of anabolic drugs. In this study, calcium phosphate nanocomposites incorporated with simvastatin (Sim) with periostin-targeting ability were designed and prepared for osteoporosis treatment. Carboxymethyl dextran (CMD) as an anionic and hydrophilic dextran derivative was used to stabilize CaP. In addition, periosteum-targeted peptide (SDSSD) was further grafted on CMD to achieve the bone targeting function. In a one-step coordination assembly strategy, hydrophobic anabolic agent Sim and SDSSD-CMD graft (SDSSD-CMD) were incorporated into the CaP nanoparticles forming SDSSD@CaP/Sim nanocomposites. The resulting SDSSD@CaP/Sim possesses uniform size, great short-term stability and excellent biocompatibility. Moreover, SDSSD@CaP/Sim exhibited a reduced release rate of Sim and showed slow-release behaviour. As anticipated, the nanocomposites exhibited bone bonding capacity in both cellular and animal studies. Besides, SDSSD@CaP/Sim achieved obviously enhanced osteoporosis treatment effect compared to direct injection of Simin vivo. Therefore, our findings highlight the potential of SDSSD-incorporated and CaP-based nanocomposites as a viable strategy to enhance the therapeutic efficacy of anabolic drugs for osteoporosis treatment.

Case report: biotin-thiamine-responsive basal ganglia disease with severe subdural hematoma on magnetic resonance imaging.

Background: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare, treatable autosomal recessive neurometabolic disorder. This condition eventually leads to severe disability and death if not treated correctly. The clinical features of BTBGD, especially those with unusual complications, are not widely known by neurologists or pediatricians.Case presentation: A 4-month-old male infant was admitted to the hospital with a history of cough for the past 7 days and convulsions of 6 h duration. Physical examination showed confusion, bilateral pupillary light reflex delays, hypertonia of limbs, and brisk tendon reflexes of the limbs. Brain magnetic resonance imaging (MRI) showed multiple abnormal signals in the bilateral basal ganglia, lobes, corpus callosum, brainstem, and brain atrophy. However, his condition continued to worsen. Computed tomography performed 3 months later showed severe subdural hematoma and effusion. Subsequently, he underwent puncture drainage; however, his condition did not improve postoperatively. Repeated MRIs showed increasing subdural hematoma and effusion, and brain atrophy. The patient was diagnosed with BTBGD following whole-genome sequencing, which identified a novel compound heterozygous mutation of SLC19A3 gene. He was treated with biotin and thiamine, and the symptoms gradually improved. Subsequent MRIs showed a decrease in the subdural hematoma and effusion and partial improvement in brain atrophy.Conclusion: To the best of our knowledge, this is the first reported case of BTBGD, complicated by severe subdural hematoma. These observations extend our understanding of the clinical features, neuroimaging spectrum, and gene mutation spectrum of BTBGD. The phenotypic spectrum and pathophysiology of BTBGD are not completely understood and need to be studied further.

Prognostic evaluation of serum osteopontin in patients with anti-MDA5 antibody-positive dermatomyositis associated interstitial lung disease.

BACKGROUND: The anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody was significantly associated with dermatomyositis associated with interstitial lung disease (DM-ILD) and poor survival in patients. However, there was no convenient and accurate biomarker can predict the poor prognosis of anti-MDA5 positive DM-ILD. This study aimed to evaluate the clinical significance of osteopontin (OPN) in anti-MDA5 positive DM-ILD patients. METHODS: The subjects were 43 patients diagnosed DM-ILD with anti-MDA5 antibody. The clinical data were obtained through a review of patient medical records. The serum samples were collected at the time of initial admission and detected for OPN concentrations and ferritin. In addition, immunohistochemistry analysis for OPN was performed on the lung sections of two patients with DM-ILD and six patients with early-stage lung cancer as normal control. RESULTS: The median value of serum OPN in patients with anti-MDA5 positive DM-ILD was 1755.65 pg/ml. Immunohistochemical findings for OPN suggested that the expression of OPN in alveolar epithelial cells and macrophages of anti-MDA5-positive ILD patients was more obvious. Significant correlations between serum OPN and ferritin levels were observed (r = 0.317, P = 0.038). Although OPN and ferritin were both associated with mortality in Univariate Cox hazards analysis, OPN was an independent predictor of the prognosis of DM-ILD rather than ferritin in Multivariate Cox hazards analysis. CONCLUSION: OPN can be expressed in lung tissues but also can exist as a secreted form in serum, and serum OPN may be a more valuable prognostic biomarker in DM-ILD patients with anti-MDA5 antibody than the serum ferritin.

Maternal health behaviors during pregnancy in rural Northwestern China.

BACKGROUND: Maternal health during pregnancy is a key input in fetal health and child development. This study aims to systematically describe the health behaviors of pregnant women in rural China and identify which subgroups of women are more likely to engage in unhealthy behaviors during pregnancy. METHODS: We surveyed 1088 pregnant women in rural northwestern China on exposure to unhealthy substances, nutritional behaviors, the timing and frequency of antenatal care, and demographic characteristics. RESULTS: Pregnant women were active in seeking antenatal care and had low rates of alcohol consumption (5.1%), exposure to toxins (4.8%), and exposure to radiation (2.9%). However, tobacco exposure was widespread (40.3%), as was low dietary diversity (61.8%), unhealthy weight gain (59.7%), unhealthy pre-pregnancy BMI (29.7%), and no folic acid intake (17.1%). Maternal education is closely linked to better health behaviors, whereas experience with a previous pregnancy is not. CONCLUSIONS: Tobacco exposure and unhealthy nutritional behaviors are common among pregnant women in rural northwestern China. The findings indicate that in the absence of professional health information, relying on experience of previous pregnancies alone may not help rural women avoid unhealthy maternal behaviors. Maternal health education campaigns targeting nutrition and tobacco exposure during pregnancy may improve maternal, fetal, and child health in rural China.

Predicting protein inter-residue contacts using composite likelihood maximization and deep learning.

BACKGROUND: Accurate prediction of inter-residue contacts of a protein is important to calculating its tertiary structure. Analysis of co-evolutionary events among residues has been proved effective in inferring inter-residue contacts. The Markov random field (MRF) technique, although being widely used for contact prediction, suffers from the following dilemma: the actual likelihood function of MRF is accurate but time-consuming to calculate; in contrast, approximations to the actual likelihood, say pseudo-likelihood, are efficient to calculate but inaccurate. Thus, how to achieve both accuracy and efficiency simultaneously remains a challenge. RESULTS: In this study, we present such an approach (called clmDCA) for contact prediction. Unlike plmDCA using pseudo-likelihood, i.e., the product of conditional probability of individual residues, our approach uses composite-likelihood, i.e., the product of conditional probability of all residue pairs. Composite likelihood has been theoretically proved as a better approximation to the actual likelihood function than pseudo-likelihood. Meanwhile, composite likelihood is still efficient to maximize, thus ensuring the efficiency of clmDCA. We present comprehensive experiments on popular benchmark datasets, including PSICOV dataset and CASP-11 dataset, to show that: i) clmDCA alone outperforms the existing MRF-based approaches in prediction accuracy. ii) When equipped with deep learning technique for refinement, the prediction accuracy of clmDCA was further significantly improved, suggesting the suitability of clmDCA for subsequent refinement procedure. We further present a successful application of the predicted contacts to accurately build tertiary structures for proteins in the PSICOV dataset. CONCLUSIONS: Composite likelihood maximization algorithm can efficiently estimate the parameters of Markov Random Fields and can improve the prediction accuracy of protein inter-residue contacts.

Correction to: Predicting protein inter-residue contacts using composite likelihood maximization and deep learning.

Following publication of the original article [1], the author explained that there are several errors in the original article.

SPOCK1 contributes to the third-generation EGFR tyrosine kinase inhibitors resistance in lung cancer.

INTRODUCTION: Explanation of the mechanism of resistance to third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the development of a novel strategy for drug resistance are imperative in third-generation EGFR-TKIs-resistant non-small cell lung cancer (NSCLC). SPOCK1 was found to be abnormally expressed in various tumors including lung cancer, however, there was no study focused on the role of SPOCK1 in third-generation EGFR-TKIs resistant lung cancer cells. METHODS AND RESULTS: We investigated the roles of SPOCK1 in NSCLC with third-generation EGFR-TKIs resistance. We showed that SPOCK1 was upregulated in the osimertinib-resistant lung cancer cells and knockdown of SPOCK1 inhibits osimertinib-resistant cells growth and overcomes resistance. Furthermore, we demonstrated that the SPOCK1 was higher in clinical NSCLC specimens compared with the normal lung tissues, and the higher expression of SPOCK1 correlated with poor prognosis. In addition, the overexpression of SPOCK1 in NSCLC tissues was positively correlated with MMP11 and TGFß1. CONCLUSION: Our study suggested that SPOCK1 could be an independent prognostic factor in NSCLC and would be a candidate for target therapy in osimertinib-resistant lung tumors.

Autocatalytic Morphology Transformation Platform for Targeted Drug Accumulation.

The precise and highly efficient drug delivery of nanomedicines into lesions remains a critical challenge in clinical translational research. Here, an autocatalytic morphology transformation platform is presented for improving the tumor-specific accumulation of drugs by kinetic control. The in situ reorganization of prodrug from nanoparticle to ß-sheet fibrous structures for targeted accumulation is based on nucleation-based growth kinetics. During multiple administrations, the autocatalytic morphology transformation can be realized for skipping slow nucleating process and constructing the bulky nanoassembly instantaneously, which has been demonstrated to induce the cumulative effect of prodrug. Furthermore, the sustained drug release from fibrous prodrug depot in the tumor site inhibits the tumor growth efficiently. The autocatalytic morphology transformation strategy in vivo offers a novel perspective for targeted delivery strategy by introducing chemical kinetics and shows great potential in disease theranostics.

Endogenous Reactive Oxygen Species-Triggered Morphology Transformation for Enhanced Cooperative Interaction with Mitochondria.

The morphology controlled molecular assemblies play vital roles in biological systems. Here we present endogenous reactive oxygen species (ROS)-triggered morphology transformation of polymer-peptide conjugates (PPCs) for cooperative interaction with mitochondria, exhibiting high tumor therapeutic efficacy. The PPCs are composed of (i) a ß-sheet-forming peptide KLVFF conjugated with poly(ethylene glycol) through ROS-cleavable thioketal, (ii) a mitochondria-targeting cytotoxic peptide KLAK, and (iii) a poly(vinyl alcohol) backbone. The self-assembled PPCs nanoparticles can enter cells and target mitochondria. Because of overgenerated ROS around mitochondria in most cancer cells, the thioketal linker can be cleaved, leading to transformation from nanoparticles to fibrous nanostructures. As a result, the locational nanofibers with exposure of KLAK exhibit enhanced multivalent cooperative interactions with mitochondria, which causes selective cytotoxicity against cancer cells and powerful tumor suppression efficacy in vivo. As the first example of ROS-triggered intracellular transformation, the locational assembly strategy in vivo may provide a new insight for disease diagnosis and therapy through enhanced interaction with targeting site.

Site-Specific Construction of Long-Term Drug Depot for Suppression of Tumor Recurrence.

Local tumor recurrence after surgical resection is a critical concern in cancer therapy, and the current treatments, such as postsurgical chemotherapy, still show undesired side effects. Here a nonimplant strategy (transformation induced localization, TIL) is presented to in situ construct long-term retentive drug depots, wherein the sustained drug release from fibrous drug depots results in highly efficient suppression of postsurgical local tumor relapse. The peptide-based prodrug nanoparticles show favorable tumor targeting and instantly reorganize into fibrous nanostructures under overexpressed enzyme, realizing the construction of long-term drug depot in the tumor site. After the resection surgery, the remnant cancer cells are still inhibited by the sustained drug release from the fibrous prodrug depot, effectively preventing postsurgical local recurrences. This TIL strategy shows great potential in cancer recurrence therapy and offers a novel perspective for constructing functional biomaterials in vivo.

Quantitative proteomic characterization of lung tissue in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, eventually fatal disease. IPF is characterized by excessive accumulation of the extracellular matrix (ECM) in the alveolar parenchyma and progressive lung scarring. The pathogenesis of IPF and whether the ECM involved in the process remain unknown. METHODS: To identify potential treatment target and ECM associated proteins that may be involved in the development of IPF, we employed isobaric tag for relative and absolute quantitation (iTRAQ) combined liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach to examine protein expression in lung tissues from IPF patients. RESULTS: A total of 662 proteins with altered expression (455 upregulated proteins and 207 downregulated proteins) were identified in lung tissue of IPF patients compared with control. KEGG pathway enrichment analysis showed that the altered proteins in lung tissue mainly belonged to the PI3K-Akt signaling, focal adhesion, ECM-receptor interaction, and carbon metabolism pathways. According to the bioinformatic definition of the matrisome, 229 matrisome proteins were identified in lung tissue. These proteins comprised the ECM of lung, of which 104 were core matrisome proteins, and 125 were matrisome-associated proteins. Of the 229 ECM quantified proteins, 56 significantly differentially expressed proteins (19 upregulated proteins and 37 downregulated proteins) were detected in IPF lung tissue samples. In addition to proteins with well-known functions such as COL1A1, SCGB1A1, TAGLN, PSEN2, TSPAN1, CTSB, AGR2, CSPG2, and SERPINB3, we identified several novel ECM proteins with unknown function deposited in IPF lung tissue including LGALS7, ASPN, HSP90AA1 and HSP90AB1. Some of these differentially expressed proteins were further verified using Western blot analysis and immunohistochemical staining. CONCLUSIONS: This study provides a list of proteomes that were detected in IPF lung tissue by iTRAQ technology combined with LC-MS/MS. The findings of this study will contribute better understanding to the pathogenesis of IPF and facilitate the development of therapeutic targets.

Microenvironment-Induced In Situ Self-Assembly of Polymer-Peptide Conjugates That Attack Solid Tumors Deeply.

In cancer treatment, the unsatisfactory solid-tumor penetration of nanomaterials limits their therapeutic efficacy. We employed an in vivo self-assembly strategy and designed polymer-peptide conjugates (PPCs) that underwent an acid-induced hydrophobicity increase with a narrow pH-response range (from 7.4 to 6.5). In situ self-assembly in the tumor microenvironment at appropriate molecular concentrations (around the IC50 values of PPCs) enabled drug delivery deeper into the tumor. A cytotoxic peptide KLAK, decorated with the pH-sensitive moiety cis-aconitic anhydride (CAA), and a cell-penetrating peptide TAT were conjugated onto poly(ß-thioester) backbones to produce PT-K-CAA, which can penetrate deeply into solid tumors owing to its small size as a single chain. During penetration in vivo, CAA responds to the weak acid, leading to the self-assembly of PPCs and the recovery of therapeutic activity. Therefore, a deep-penetration ability for enhanced cancer therapy is provided by this in vivo assembly strategy.

RaptorX-Angle: real-value prediction of protein backbone dihedral angles through a hybrid method of clustering and deep learning.

BACKGROUND: Protein dihedral angles provide a detailed description of protein local conformation. Predicted dihedral angles can be used to narrow down the conformational space of the whole polypeptide chain significantly, thus aiding protein tertiary structure prediction. However, direct angle prediction from sequence alone is challenging. RESULTS: In this article, we present a novel method (named RaptorX-Angle) to predict real-valued angles by combining clustering and deep learning. Tested on a subset of PDB25 and the targets in the latest two Critical Assessment of protein Structure Prediction (CASP), our method outperforms the existing state-of-art method SPIDER2 in terms of Pearson Correlation Coefficient (PCC) and Mean Absolute Error (MAE). Our result also shows approximately linear relationship between the real prediction errors and our estimated bounds. That is, the real prediction error can be well approximated by our estimated bounds. CONCLUSIONS: Our study provides an alternative and more accurate prediction of dihedral angles, which may facilitate protein structure prediction and functional study.

Improving residue-residue contact prediction via low-rank and sparse decomposition of residue correlation matrix.

Strategies for correlation analysis in protein contact prediction often encounter two challenges, namely, the indirect coupling among residues, and the background correlations mainly caused by phylogenetic biases. While various studies have been conducted on how to disentangle indirect coupling, the removal of background correlations still remains unresolved. Here, we present an approach for removing background correlations via low-rank and sparse decomposition (LRS) of a residue correlation matrix. The correlation matrix can be constructed using either local inference strategies (e.g., mutual information, or MI) or global inference strategies (e.g., direct coupling analysis, or DCA). In our approach, a correlation matrix was decomposed into two components, i.e., a low-rank component representing background correlations, and a sparse component representing true correlations. Finally the residue contacts were inferred from the sparse component of correlation matrix. We trained our LRS-based method on the PSICOV dataset, and tested it on both GREMLIN and CASP11 datasets. Our experimental results suggested that LRS significantly improves the contact prediction precision. For example, when equipped with the LRS technique, the prediction precision of MI and mfDCA increased from 0.25 to 0.67 and from 0.58 to 0.70, respectively (Top L/10 predicted contacts, sequence separation: 5 AA, dataset: GREMLIN). In addition, our LRS technique also consistently outperforms the popular denoising technique APC (average product correction), on both local (MI_LRS: 0.67 vs MI_APC: 0.34) and global measures (mfDCA_LRS: 0.70 vs mfDCA_APC: 0.67). Interestingly, we found out that when equipped with our LRS technique, local inference strategies performed in a comparable manner to that of global inference strategies, implying that the application of LRS technique narrowed down the performance gap between local and global inference strategies. Overall, our LRS technique greatly facilitates protein contact prediction by removing background correlations. An implementation of the approach called COLORS (improving COntact prediction using LOw-Rank and Sparse matrix decomposition) is available from http://protein.ict.ac.cn/COLORS/.

pH-Sensitive Polymeric Nanoparticles with Gold(I) Compound Payloads Synergistically Induce Cancer Cell Death through Modulation of Autophagy.

Various nanomaterials have been demonstrated as autophagy inducers owing to their endocytosis cell uptake pathway and impairment of lysosomes. pH-dependent nanomaterials as drug delivery systems that are capable of dissociating in weakly acidic lysosomal environment (pH 4-5) and consequently releasing the payloads into the cytoplasm have been paid extensive attention, but their autophagy-modulating effects are less reported so far. In this study, we report pH-sensitive micelle-like nanoparticles (NPs) that self-assembled from poly(ß-amino ester)s to induce cell autophagy. By encapsulation of gold(I) compounds (Au(I)) into hydrophobic domains of NPs, the resultant Au(I)-loaded NPs (Au(I)⊂NPs) shows synergistic cancer cell killing performance. The Au(I)⊂NPs enter cells through endocytosis pathway and accumulate into acidic lysosomes. Subsequently, the protonation of tertiary amines of poly(ß-amino ester)s triggers the dissociation of micelles, damages the lysosomes, and blocks formation of autolysosomes from fusion of lysosomes with autophagosomes. In addition, Au(I) preferentially inhibits thioredoxin reductase (TrxR) in MCF-7 human breast cancer cells that directly links to up-regulate reactive oxygen species (ROS) and consequently induce autophagy and apoptosis. The blockade of autophagy leads to excessive depletion of cellular organelles and essential proteins and ultimately results in cell death. Therefore, pH-sensitive polymeric nanoparticles with gold(I) compound payloads can synergistically induce cancer cell death through regulation of autophagy. Identification of the pH-sensitive nanomaterials for synergistically inducing cell death through regulation autophagy may open a new avenue for cancer therapy.

pH-Sensitive polymer assisted self-aggregation of bis(pyrene) in living cells in situ with turn-on fluorescence.

Supramolecular self-assemblies with various nanostructures in organic and aqueous solutions have been prepared with desired functions. However, in situ construction of self-assembled superstructures in physiological conditions to achieve expected biological functions remains a challenge. Here, we report a supramolecular system to realize the in situ formation of nanoaggregates in living cells. The bis(pyrene) monomers were dispersed inside of hydrophobic domains of pH-sensitive polymeric micelles and delivered to the lysosomes of cells. In the acidic lysosomes, the bis(pyrene) monomers were released and self-aggregated with turn-on fluorescence. We envision this strategy for in situ construction of supramolecular nanostructures in living cells will pave the way for molecular diagnostics in the future.