Diarylheptanoid 35d overcomes EGFR TKI resistance by inducing hsp70-mediated lysosomal degradation of EGFR in EGFR-mutant lung adenocarcinoma.

Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients often respond to EGFR tyrosine kinase inhibitors (TKIs) initially but eventually develop resistance to TKIs. The switch of EGFR downstream signaling from TKI-sensitive to TKI-insensitive is a critical mechanism-driving resistance to TKIs. Identification of potential therapies to target EGFR effectively is a potential strategy to treat TKI-resistant LUADs. In this study, we developed a small molecule diarylheptanoid 35d, a curcumin derivative, that effectively suppressed EGFR protein expression, killed multiple TKI-resistant LUAD cells in vitro, and suppressed tumor growth of EGFR-mutant LUAD xenografts with variant TKI-resistant mechanisms including EGFR C797S mutations in vivo. Mechanically, 35d triggers heat shock protein 70-mediated lysosomal pathway through transcriptional activation of several components in the pathway, such as HSPA1B, to induce EGFR protein degradation. Interestingly, higher HSPA1B expression in LUAD tumors associated with longer survival of EGFR-mutant, TKI-treated patients, suggesting the role of HSPA1B on retarding TKI resistance and providing a rationale for combining 35d with EGFR TKIs. Our data showed that combination of 35d significantly inhibits tumor reprogression on osimertinib and prolongs mice survival. Overall, our results suggest 35d as a promising lead compound to suppress EGFR expression and provide important insights into the development of combination therapies for TKI-resistant LUADs, which could have translational potential for the treatment of this deadly disease.

Multihierarchical Regulation To Achieve Quantum Dot Nanospheres with a Photoluminescence Quantum Yield Close to 100.

Quantum dots (QDs) exhibit superior brightness and photochemical stability, making them the preferred option for highly sensitive single-molecule detection compared with fluorescent dyes or proteins. Nevertheless, their high surface energy leads to nonspecific adsorption and poor colloidal stability. In the past decades, we have found that QD-based fluorescent nanoparticles (FNs) can not only address these limitations but also enhance detection sensitivity. However, the photoluminescence quantum yield (PLQY) of FNs is significantly lower compared with that of original QDs. It is urgent to develop a strategy to solve the issue, aiming to further enhance detection sensitivity. In this study, we found that the decrease of PLQY of FNs prepared by free radical polymerization was attributed to two factors: (1) generation of defects that can cause nonradiative transitions resulting from QD-ligands desorption and QD-shell oxidation induced by free radicals; (2) self-absorption resulting from aggregation caused by incompatibility of QDs with polymers. Based on these, we proposed a multihierarchical regulation strategy that includes: (1) regulating QD-ligands; (2) precisely controlling free radical concentration; and (3) constructing cross-linked structures of polymer to improve compatibility and to reduce the formation of surface defects. It is crucial to emphasize that the simultaneous coordination of multiple factors is essential. Consequently, a world-record PLQY of 97.6% for FNs was achieved, breaking through the current bottleneck at 65%. The flexible application of this regulatory concept paves the way for the large-scale production of high-brightness QD-polymer complexes, enhancing their potential applications in sensitive biomedical detection.

Enhancing Circularly Polarized Luminescence in Quantum Dots through Chiral Coordination-Mediated Growth at the Liquid/Liquid Interface.

Here, we develop a novel methodology for synthesizing chiral CdSe@ZnS quantum dots (QDs) with enhanced circularly polarized luminescence (CPL) by incorporating l-/d-histidine (l-/d-His) ligands during ZnS shell growth at the water/oil interface. The resulting chiral QDs exhibit exceptional absolute photoluminescence quantum yield of up to 67.2%, surpassing the reported limits of 40.0% for chiral inorganic QDs, along with absorption dissymmetry factor (|gabs|) and luminescence dissymmetry factor (|glum|) values of 10-2, exceeding the range of 10-5-10-3 and 10-4-10-2, respectively. Detailed investigations of the synthetic pathway reveal that the interface, as a binary synthetic environment, facilitates the coordinated ligand exchange and shell growth mediated by chiral His-Zn2+ coordination complexes, leading to a maximum fluorescent brightness and chiroptical activities. The growth process, regulated by the His-Zn2+ coordination complex, not only reduces trap states on the CdSe surface, thereby enhancing the fluorescence intensity, but also significantly promotes the orbital hybridization between QDs and chiral ligands, effectively overcoming the shielding effect of the wide bandgap shell and imparting pronounced chirality. The proposed growth pathway elucidates the origin of chirality and provides insights into the regulation of the CPL intensity in chiral QDs. Furthermore, the application of CPL QDs in multilevel anticounterfeiting systems overcomes the limitations of replication in achiral fluorescence materials and enhances the system's resistance to counterfeiting, thus opening new opportunities for chiral QDs in optical anticounterfeiting and intelligent information encryption.

Acid-Resistant Near-Infrared II Ag2Se Quantum Dots for Gastrointestinal Imaging.

With the development of near-infrared II (NIR-II) fluorescence imaging, Ag2Se quantum dots (QDs) have become promising label candidates due to their negligible toxicity and narrow band gap. Despite their potential for gastrointestinal (GI) imaging, the application of Ag2Se QDs still presents significant challenges due to issues such as fluorescence extinction or poor stability in the complex digestive microenvironment. Herein, we have proposed a novel approach to the continuous production of Se precursors using glutathione (GSH) as the reductant under acidic conditions, realizing the continuous growth of water-dispersible Ag2Se QDs. The Ag2Se QDs emitting at 600-1100 nm have been successfully synthesized. Meanwhile, the silver-rich surface of the synthesized NIR-II Ag2Se QDs has been passivated well with the dense GSH, resulting in exceptional colloidal stability and photostability and endowing them with acid resistance. As a result, the obtained NIR-II Ag2Se QDs have exhibited remarkable stability in gastric acid, thus enabling their utilization for long-term real-time monitoring of GI peristalsis via NIR-II fluorescence imaging. Moreover, in contrast to conventional barium meal-based X-ray imaging, NIR-II fluorescence imaging with as-prepared NIR-II Ag2Se QDs can offer clearer visualization of fine intestinal structures, with a width as small as 1.07 mm. The developed strategy has offered a new opportunity for the synthesis of acid-resistant nanocrystals, and the acid-resistant, low-toxicity, and biocompatible NIR-II Ag2Se QDs synthesized in this work show a great promise for GI imaging and diagnosis of GI diseases in vivo.

Redox Imbalance Triggered Intratumoral Cascade Reaction for Tumor "turn on" Imaging and Synergistic Therapy.

The redox homeostasis in tumors enhances their antioxidant defense ability, limiting reactive oxygen species mediated tumor therapy efficacy. The development of strategies for specific and continuous disruption of the redox homeostasis in tumor cells facilitates the improvement of the cancer therapeutic effect by promoting the apoptosis of tumor cells. Herein, a responsively biodegradable targeting multifunctional integrated nanosphere (HDMn-QDs/PEG-FA) is designed to enhance the anti-tumor efficacy by triggering intratumoral cascade reactions to effectively disrupt intracellular redox homeostasis. Once HDMn-QDs/PEG-FA enters tumor cells, manganese dioxide (MnO2 ) shell on the surface of nanosphere consumes glutathione (GSH) to produce Mn2+ , enabling enhanced chemodynamic therapy (CDT) via a Fenton-like reaction and T1 -weighted magnetic resonance imaging. Meanwhile, the degradation of MnO2 can also cause the fluorescence recovery of quantum dots conjugated on the surface of the shell, realizing "turn-on" fluorescence imaging. In addition, the doxorubicin is released because of the cleavage of the embedded SS bond in the hybrid core framework by GSH. A superior synergistic therapeutic efficiency combined CDT and chemotherapy is shown by HDMn-QDs/PEG-FA in vivo. The tumor-inhibition rate reaches to 94.8% and does not cause normal tissue damage due to the good targeting and tumor microenvironment-specific response.

PLAGL1 is associated with prognosis and cell proliferation in pancreatic adenocarcinoma.

BACKGROUND: Emerging evidence has shown the crucial roles of pleomorphic adenoma gene (PLAG) family genes in multiple cancers. However, their functions and mechanisms in pancreatic adenocarcinoma (PAAD) remain poorly understood. METHODS: We analyzed the expression levels of PLAG family genes in both The Cancer Genome Atlas (TCGA) database and a Gene Expression Omnibus (GEO) database, and confirmed the results in our three independent cohorts of 382 PAAD tissues and 362 adjacent nontumor pancreatic tissues. Integrated analyses were carried out to explore the function, mechanism and prognostic value of the selected PLAG family gene in PAAD patients. RESULTS: By analyzing the TCGA and GEO databases, PLAGL1 was identified to be downregulated in PAAD tissues, and its decreasing levels of both mRNA and protein were verified in our three independent PAAD cohorts. PLAGL1 expression was inversely correlated with clinicopathological factors including the Ki67+ cell rate and pathologic stage. Further GSEA of the TCGA-PAAD cohort demonstrated that multiple signaling pathways implicated in cell proliferation were enriched in the lower PLAGL1 expressing PAAD group. Moreover, we demonstrated that PLAGL1 expression was obviously negatively associated with patients' overall survival outcome in both the TCGA-PAAD cohort and our verification cohorts. Additionally, through MTS and BrdU assays, we further demonstrated in vitro that PLAGL1 had the impact of preventing the proliferation of pancreatic cancer cells. CONCLUSIONS: Our present study suggested that downregulated PLAGL1 might act as a biomarker in predicts poor prognosis and one of important factors in increasing cell proliferation in PAAD. This study provides us with a novel prognostic marker and therapeutic strategy for PAAD, which deserves further study.

Capture of small clusters by ligand-solvent interaction.

Clusters are considered to become increasingly significant for elaborating the nanocrystal's formation mechanism. However, capturing the clusters with high chemical potential is challenging because of the lack of effective strategies. In this work, the key role of ligand-solvent interaction has been revealed for the stabilization of clusters in silver telluride synthesis. The Flory interaction coefficient that comprehensively regards the temperature and dispersion, polarity, and hydrogen bonding of the solvent has been used to evaluate the ligand-solvent interaction and thus assist in the design of synthetic systems. Small silver telluride clusters have been successfully captured, and the composition of the smallest cluster is determined as Ag7Te8(SCy)2 (SCy represents the ligand). This work provides new insights into the design of cluster/nanocrystal synthesis systems and paves the way to revealing the mechanism of precursor-cluster-nanocrystal conversion.

Defining raft domains in the plasma membrane.

Many plasma membrane (PM) functions depend on the cholesterol concentration in the PM in strikingly nonlinear, cooperative ways: fully functional in the presence of physiological cholesterol levels (35~45 mol%), and nonfunctional below 25 mol% cholesterol; namely, still in the presence of high concentrations of cholesterol. This suggests the involvement of cholesterol-based complexes/domains formed cooperatively. In this review, by examining the results obtained by using fluorescent lipid analogs and avoiding the trap of circular logic, often found in the raft literature, we point out the fundamental similarities of liquid-ordered (Lo)-phase domains in giant unilamellar vesicles, Lo-phase-like domains formed at lower temperatures in giant PM vesicles, and detergent-resistant membranes: these domains are formed by cooperative interactions of cholesterol, saturated acyl chains, and unsaturated acyl chains, in the presence of >25 mol% cholesterol. The literature contains evidence, indicating that the domains formed by the same basic cooperative molecular interactions exist and play essential roles in signal transduction in the PM. Therefore, as a working definition, we propose that raft domains in the PM are liquid-like molecular complexes/domains formed by cooperative interactions of cholesterol with saturated acyl chains as well as unsaturated acyl chains, due to saturated acyl chains' weak multiple accommodating interactions with cholesterol and cholesterol's low miscibility with unsaturated acyl chains and TM proteins. Molecules move within raft domains and exchange with those in the bulk PM. We provide a logically established collection of fluorescent lipid probes that preferentially partition into raft and non-raft domains, as defined here, in the PM.

In Situ Self-Sorting Peptide Assemblies in Living Cells for Simultaneous Organelle Targeting.

Self-sorting is a common phenomenon in eukaryotic cells and represents one of the versatile strategies for the formation of advanced functional materials; however, developing artificial self-sorting assemblies within living cells remains challenging. Here, we report on the GSH-responsive in situ self-sorting peptide assemblies within cancer cells for simultaneous organelle targeting to promote combinatorial organelle dysfunction and thereby cell death. The self-sorting system was created via the design of two peptides E3C16E6 and EVMSeO derived from lipid-inspired peptide interdigitating amphiphiles and peptide bola-amphiphiles, respectively. The distinct organization patterns of the two peptides facilitate their GSH-induced self-sorting into isolated nanofibrils as a result of cleavage of disulfide-connected hydrophilic domains or reduction of selenoxide groups. The GSH-responsive in situ self-sorting in the peptide assemblies within HeLa cells was directly characterized by super-resolution structured illumination microscopy. Incorporation of the thiol and ER-targeting groups into the self-sorted assemblies endows their simultaneous targeting of endoplasmic reticulum and Golgi apparatus, thus leading to combinatorial organelle dysfunction and cell death. Our results demonstrate the establishment of the in situ self-sorting peptide assemblies within living cells, thus providing a unique platform for drug targeting delivery and an alternative strategy for modulating biological processes in the future.

Immunoprofiling of Severity and Stage of Bacterial Infectious Diseases by Ultrabright Fluorescent Nanosphere-Based Dyad Test Strips.

Bacterial infectious diseases are common clinical diseases that seriously threaten human health, especially in countries and regions with poor environmental hygiene. Due to the lack of characteristic clinical symptoms and signs, it is a challenge to distinguish a bacterial infection from other infections, leading to misdiagnosis and antibiotic overuse. Therefore, there is an urgent need to develop a specific method for detection of bacterial infections. Herein, utilizing ultrabright fluorescent nanospheres (FNs) as reporters, immunochromatographic dyad test strips are developed for the early detection of bacterial infections and distinction of different stages of bacterial infectious diseases in clinical samples. C-reactive protein (CRP) and heparin-binding protein (HBP) are quantified and assayed because their levels in plasma are varied dynamically and asynchronously during the progression of the disease. The detection limits of CRP and HBP can reach as low as 0.51 and 0.65 ng/mL, respectively, due to the superior fluorescence intensity of each FN, which is 570 times stronger than that of a single quantum dot. The assay procedure can be achieved in 22 min, fully meeting the needs of rapid and ultrasensitive detection in the field. This constructed strip has been successfully used to profile the stage and severity of bacterial infections by monitoring the levels of CRP and HBP in human plasma samples, showing great potential as a point-of-care biosensor for clinical diagnosis. In addition to bacterial infections, the developed ultrabright FN-based point-of-care testing can be readily expanded for rapid, quantitative, and ultrasensitive detection of other trace substances in complex systems.

Investigation of citrinin and monacolin K gene clusters variation among pigment producer Monascus species.

The filamentous fungi Monascus spp. have been widely used in the production of food colorants. However, the presence of mycotoxin citrinin and the antihypercholestrolemia agent monacolin K in Monascus-fermented products (MFPs) has raised food safety concerns. Here we de novo-sequenced the genomes of 26 Monascus species and proposed an unprecedented classification system, consist of sections A, B and C, according to the biosynthetic gene clusters (BGCs) distribution and phylogeny results. Based on the absence of citrinin gene cluster, section B species were genetically incapable of synthesizing citrinin. A distinguished section A strain named Monascus sanguineus was believed to be a promising food-pigment-producer particularly owing to the simultaneous inactivation of citrinin and monacolin K clusters. Interestingly, gene losses within Monascus secondary metabolism gene clusters were broadly discovered, which may convey a selective advantage in nutrients and energy competition to support the strong pigment-producing ability. Overall, our sectional delimitation system will reshape the industrial strategies for this economically important fungus.

Single-Virus Tracking: From Imaging Methodologies to Virological Applications.

Uncovering the mechanisms of virus infection and assembly is crucial for preventing the spread of viruses and treating viral disease. The technique of single-virus tracking (SVT), also known as single-virus tracing, allows one to follow individual viruses at different parts of their life cycle and thereby provides dynamic insights into fundamental processes of viruses occurring in live cells. SVT is typically based on fluorescence imaging and reveals insights into previously unreported infection mechanisms. In this review article, we provide the readers a broad overview of the SVT technique. We first summarize recent advances in SVT, from the choice of fluorescent labels and labeling strategies to imaging implementation and analytical methodologies. We then describe representative applications in detail to elucidate how SVT serves as a valuable tool in virological research. Finally, we present our perspectives regarding the future possibilities and challenges of SVT.

Comparison of early postoperative outcomes between omega-like duct-to-mucosa pancreatojejunostomy and conventional duct-to-mucosa pancreatojejunostomy after pancreaticoduodenectomy.

BACKGROUND: Pancreatic fistula is a life-threatening complication of pancreaticoduodenectomy. Omega-like duct-to-mucosa pancreatojejunostomy is a novel technique which helps reduce the risk of fistulation. This study aimed to compare early postoperative outcomes of omega-like and conventional pancreatojejunostomy. METHODS: A retrospective single-centre cohort study comparing outcomes of adult patients who underwent open pancreatoduodenectomy with conventional (CDMP) or omega-like duct-to-mucosa pancreatojejunostomy (ODMP) between 1 January 2015 and 31 December 2019. The primary outcome measure was the pancreatic fistula rate. RESULTS: 440 patients were included in this study of whom 233 underwent CDMP and 207 ODMP. The rate of clinically relevant pancreatic fistula (grade B/C) was significantly higher after CDMP than ODMP (18.5% vs. 10.6%, P = 0.021). 153 patients in CDMP group and 99 patients in ODMP group developed one or more complications (65.7% vs. 47.8%, P = 0.004). The average hospitalization expenses were numerically decreased in ODMP group, although this was not statistically significant (120,000 ± 42,000 [Chinese Yuan] vs. 100,000 ± 40,000 [Chinese Yuan] or 18,581 ± 6503 [United States Dollar] vs. 15,484 ± 6194 [United States Dollar], P = 0.402). CONCLUSION: ODMP may reduce the incidence of pancreatic fistula and other early postoperative complications after pancreatoduodenectomy.

In-Sequence High-Specificity Dual-Reporter Unlocking of Fluorescent Probe Enables the Precise Identification of Atherosclerotic Plaques.

The formation of atherosclerotic plaques is the root cause of various cardiovascular diseases (CVDs). Effective CVD interventions thus call for precise identification of the plaques to aid clinical assessment, diagnosis, and treatment of such diseases. In this study, we introduce a dual-target sequentially activated fluorescence reporting system, termed in-sequence high-specificity dual-reporter unlocking (iSHERLOCK), to precisely identify the atherosclerotic plaques in vivo and ex vivo. ISHERLOCK was achieved by creating a three-in-one fluorescent probe that permits highly specific and sensitive detection of lipid droplets and hypochlorous acid via "off-on" and ratiometric readouts, respectively. Based on this format, the upregulated lipid accumulation and oxidative stress-the two hallmarks of atherosclerosis (AS)-were specifically measured in the atherosclerotic plaques, breaking through the barrier of precise tissue biopsy of AS and thus aiding effective CVD stewardship.

Breaking through the Size Control Dilemma of Silver Chalcogenide Quantum Dots via Trialkylphosphine-Induced Ripening: Leading to Ag2Te Emitting from 950 to 2100 nm.

Ag2Te is one of the most promising semiconductors with a narrow band gap and low toxicity; however, it remains a challenge to tune the emission of Ag2Te quantum dots (QDs) precisely and continuously in a wide range. Herein, Ag2Te QDs emitting from 950 to 2100 nm have been synthesized via trialkylphosphine-controlled growth. Trialkylphosphine has been found to induce the dissolution of small-sized Ag2Te QDs due to its stronger ability to coordinate to the Ag ion than that of 1-octanethiol, predicated by the density functional theory. By controlling this dissolution effect, the monomer supply kinetics can be regulated, achieving precise size control of Ag2Te QDs. This synthetic strategy results in state-of-the-art silver-based QDs with emission tunability. Only by taking advantage of such an ultrawide emission has the sizing curve of Ag2Te been obtained. Moreover, the absolute photoluminescence quantum yield of Ag2Te QDs can reach 12.0% due to their well-passivated Ag-enriched surface with a density of 5.0 ligands/nm2, facilitating noninvasive in vivo fluorescence imaging. The high brightness in the long-wavelength near-infrared (NIR) region makes the cerebral vasculature and the tiny vessel with a width of only 60 µm clearly discriminable. This work reveals a nonclassical growth mechanism of Ag2Te QDs, providing new insight into precisely controlling the size and corresponding photoluminescence properties of semiconductor nanocrystals. The ultrasmall, low-toxicity, emission-tunable, and bright NIR-II Ag2Te QDs synthesized in this work offer a tremendous promise for multicolor and deep-tissue in vivo fluorescence imaging.

Enzymatic dimerization in the biosynthetic pathway of microbial natural products.

Covering: up to August 2020The dramatic increase in the identification of dimeric natural products generated by microorganisms and plants has played a significant role in drug discovery. The biosynthetic pathways of these products feature inherent dimerization reactions, which are valuable for biosynthetic applications and chemical transformations. The extraordinary mechanisms of the dimerization of secondary metabolites should advance our understanding of the uncommon chemical rules for natural product biosynthesis, which will, in turn, accelerate the discovery of dimeric reactions and molecules in nature and provide promising strategies for the total synthesis of natural products through dimerization. This review focuses on the enzymes involved in the dimerization in the biosynthetic pathway of microbial natural products, with an emphasis on cytochrome P450s, laccases, and intermolecular [4 + 2] cyclases, along with other atypical enzymes. The identification, characterization, and catalytic landscapes of these enzymes are also introduced.

Correction: A powerful azomethine ylide route mediated by TiO2 photocatalysis for the preparation of polysubstituted imidazolidines.

Correction for 'A powerful azomethine ylide route mediated by TiO2 photocatalysis for the preparation of polysubstituted imidazolidines' by Anan Liu et al., Org. Biomol. Chem., 2021, 19, 2192-2197, DOI: .

A powerful azomethine ylide route mediated by TiO2 photocatalysis for the preparation of polysubstituted imidazolidines.

Lewis- and Brønsted-acid catalyzed 1,3-dipolar cycloaddition between azomethine ylides and unsaturated compounds is an important strategy to construct five-membered N-heterocycles. However, such a catalytic route usually demands substrates with an electron-withdrawing group (EWG) to facilitate the reactivity. Herein, we report a TiO2 photocatalysis strategy that can conveniently prepare five-membered N-heterocyclic imidazolidines from a common imine (N-benzylidenebenzylamine) and alcohols along the route of 1,3-dipolaron azomethine ylide but without pre-installed EWG substituents on the substrates. Our EPR results uncovered the previously unknown mutual interdependence between an azomethine ylide and TiO2 photo-induced hvb+/ecb- pair. This transformation exhibited a broad scope with 21 successful examples and could be scaled up to the gram level.

Long noncoding RNA-mRNA expression profiles and validation in pancreatic neuroendocrine neoplasms.

BACKGROUND: Pancreatic neuroendocrine neoplasms (pNENs) are a group of endocrine tumours arising in the pancreas and deemed to be the most common neuroendocrine tumours. The pathogenesis of pNENs remains unknown. Long noncoding RNAs (lncRNAs) are aberrantly expressed in cancers. The functional roles of lncRNAs and lncRNA-mRNA expression profiles in pNENs are undefined. The aim of this study was to identify the lncRNA and mRNA expression profiles and explore the lncRNA-mRNA co-expression networks associated with the pNENs carcinogenesis. METHOD: Differentially expressed lncRNA and mRNA in pNENs tissues from adjacent tissues were detected using human lncRNA microarray V3.0 containing 30 586 lncRNA and 26 109 coding transcripts. Probable functions for lncRNAs and mRNAs were predicted according to lncRNA-mRNA network. RESULTS: The microarray identified 2080 lncRNAs and 1771 mRNAs in pNENs tumours differentially expressed compared with the adjacent tissues. The GO terms and KEGG pathway annotation data indicated that cell projection morphogenesis, cell adhesion molecules pathway, PI3K-AKT signalling pathway, focal adhesion pathway, neuroactive ligand-receptor interaction pathways and Ras signalling pathways were significantly associated with the pNENs tumorigenesis. Co-expression network analysis revealed the differential interactions between lncRNAs and mRNAs in pNENs tumours and adjacent tissues. The genes, situated at the important nodes of the co-expression network, include ICOSLG, ENST00000512077, FGF8 and ENST00000511918. CONCLUSIONS: There were significant differences in lncRNA and mRNA expression between pNEN tumours and adjacent tissues, and these differences were associated with tumorigenesis through multiple biological processes and signalling pathways. These results provided important insights regarding lncRNA in pNENs pathogenesis and provide potential therapeutic targets.

MnCaCs-Biomineralized Oncolytic Virus for Bimodal Imaging-Guided and Synergistically Enhanced Anticancer Therapy.

Oncolytic adenovirus (OA) is an ideal candidate for clinical anticancer treatment, because it can specifically replicate in tumor cells with high titer. However, its systemic administration is still hindered, because of severely compromised antitumor efficacy. Herein, an engineered OA was innovatively developed by enwrapping OA with calcium and manganese carbonates (MnCaCs) biomineral shell, which could protect the virus from removal of the host immune system and prolong its in vivo circulation. Upon accumulating in tumor sites, MnCaCs readily dissolved under the acidic microenvironment, releasing Mn2+ that could convert endogenous H2O2 into oxygen (O2) and then enhance the duplication ability of OA, thus significantly increased the antitumor efficacy. Meanwhile, Mn2+ and the increased O2 individually endowed the T1 modal magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) feasibility, providing real-time monitoring information for the therapy. This versatile engineered OA demonstrated its promise for visible and efficient oncolytic virotherapy by systemic administration.