Long-read sequencing identifies novel structural variations in colorectal cancer.

Structural variations (SVs) are a key type of cancer genomic alterations, contributing to oncogenesis and progression of many cancers, including colorectal cancer (CRC). However, SVs in CRC remain difficult to be reliably detected due to limited SV-detection capacity of the commonly used short-read sequencing. This study investigated the somatic SVs in 21 pairs of CRC samples by Nanopore whole-genome long-read sequencing. 5200 novel somatic SVs from 21 CRC patients (494 SVs / patient) were identified. A 4.9-Mbp long inversion that silences APC expression (confirmed by RNA-seq) and an 11.2-kbp inversion that structurally alters CFTR were identified. Two novel gene fusions that might functionally impact the oncogene RNF38 and the tumor-suppressor SMAD3 were detected. RNF38 fusion possesses metastasis-promoting ability confirmed by in vitro migration and invasion assay, and in vivo metastasis experiments. This work highlighted the various applications of long-read sequencing in cancer genome analysis, and shed new light on how somatic SVs structurally alter critical genes in CRC. The investigation on somatic SVs via nanopore sequencing revealed the potential of this genomic approach in facilitating precise diagnosis and personalized treatment of CRC.

PltDB: a blood platelets-based gene expression database for disease investigation.

MOTIVATION: Molecular profiling of blood-based liquid biopsies is a promising disease detection method, which overcomes the limitations of invasive diagnostic strategies. Recently, gene expression profiling of platelets reportedly provides valuable resource for developing new biomarkers for the detection of diseases, including cancer. However, there is no database containing RNAs in platelets. RESULTS: In this study, we constructed PltDB (http://www.pltdb-hust.com), a blood platelets-based gene expression database featuring integration and visualization of RNA expression profiles based on RNA-seq and microarray data spanning both normal individuals and patients with different diseases. PltDB currently contains the expression landscape of mRNAs, lncRNAs, circRNAs and miRNAs in platelets from patients with different disease types and healthy controls. Moreover, PltDB provides users with the tools for visualizing results of comparison and correlation analysis and for downloading expression profiles and analysis results. A submission interface for the scientific community is also embraced for uploading novel RNA expression profiles derived from platelet samples. PltDB will offer a comprehensive review of the clinical use of platelets, overcome technical problems when analyzing data from diverse studies and serve as a powerful platform for developing new blood biomarkers. AVAILABILITY AND IMPLEMENTATION: PltDB is accessible at http://www.pltdb-hust.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Secreted AGR2 promotes invasion of colorectal cancer cells via Wnt11-mediated non-canonical Wnt signaling.

Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is present in both intracellular and extracellular compartments. Although AGR2 is overexpressed in various human cancers and reported to promote aggressive tumor features, little is known regarding AGR2's extracellular functions during tumorigenesis. Here, we demonstrate that secreted AGR2 promotes cell migration and metastasis of colorectal cancer (CRC) in vitro and in vivo. Mechanistically, secreted AGR2 elevated Wnt11 expression, triggering non-canonical Wnt signaling: the Ca2+/Calmodulin-dependent protein kinase II (CaMKII) and c-jun amino-terminal kinase (JNK) pathways. Knockdown of Wnt11 or pretreatment with CaMKII and JNK inhibitors reversed the secreted AGR2's migration-promoting effect. Further studies revealed that AGR2 antagonized canonical Wnt/ß-catenin signaling via activating CaMKII. Collectively, our study uncovers a critical role of Wnt11-mediated non-canonical Wnt signaling (CaMKII and JNK pathways) in secreted AGR2's promoted migration of CRC cells. These results raise the possibility that secreted AGR2 may be a potential therapeutic target towards inhibiting CRC metastasis.

Synergized Multimodal Therapy for Safe and Effective Reversal of Cancer Multidrug Resistance Based on Low-Level Photothermal and Photodynamic Effects.

Despite the therapeutic usefulness of near-infrared irradiation (NIR)-induced potent photothermal effects (PTE) and photodynamic effects (PDE), they inevitably damage normal tissues, often posing threat to life when treating tumors adjacent to key organs or major blood vessels. In this study, the frequently overlooked, "weak" PTE and PDE (no killing capability) are employed to synergize chemotherapy against multidrug resistance (MDR) without impairing normal tissues. An NIR-responsive nanosystem, gold (Au)-nanodot-decorated hollow carbon nanospheres coated with hyaluronic acid, is synthesized as a doxorubicin (DOX) carrier with excellent photothermal and photodynamic properties. Upon low-level infrared irradiation, the mild heat of weak PTE moderately boosts DOX unloading, meanwhile the weak PDE moderately disturbs the P-glycoprotein function for retaining intracellular DOX by impairing mitochondrial ATP production. These two "moderate" alterations are quantitatively and functionally sufficient to augment the efficacy of chemotherapy in reversing MDR without damaging neighboring tissue. Thus, this work creates a gold-dot-decorated nanocarbon spheres based nanosystem for trimodal therapy, reveals the therapeutic value of the frequently ignored weak PTE/PDE, and demonstrates that synergizing with chemotherapy to overcome drug resistance does not necessarily require potent PTE/PDE.

A Graphene Composite Film Based Wearable Far-Infrared Therapy Apparatus (GRAFT) for Effective Prevention of Postoperative Peritoneal Adhesion.

Postoperative peritoneal adhesion (PPA) is the most frequent complication after abdominal surgery. Current anti-adhesion strategies largely rely on the use of physical separating barriers creating an interface blocking peritoneal adhesion, which cannot reduce inflammation and suffers from limited anti-adhesion efficacy with unwanted side effects. Here, by exploiting the alternative activated macrophages to alleviate inflammation in adhesion development, a flexible graphene-composite-film (F-GCF) generating far-infrared (FIR) irradiation that effectively modulates the macrophage phenotype toward the anti-inflammatory M2 type, resulting in reduced PPA formation, is designed. The anti-adhesion effect of the FIR generated by F-GCF is determined in the rat abdominal wall abrasion-cecum defect models, which exhibit reduced incidence and area of PPA by 67.0% and 92.1% after FIR treatment without skin damage, significantly superior to the clinically used chitosan hydrogel. Notably, within peritoneal macrophages, FIR reduces inflammation reaction and promotes tissue plasminogen activator (t-PA) level via the polarization of peritoneal macrophages through upregulating Nr4a2 expression. To facilitate clinical use, a wirelessly controlled, wearable, F-GCF-based FIR therapy apparatus (GRAFT) is further developed and its remarkable anti-adhesion ability in the porcine PPA model is revealed. Collectively, the physical, biochemical, and in vivo preclinical data provide compelling evidence demonstrating the clinical-translational value of FIR in PPA prevention.

ATG5-regulated CCL2/MCP-1 production in myeloid cells selectively modulates anti-malarial CD4+ Th1 responses.

Parasite-specific CD4+ Th1 cell responses are the predominant immune effector for controlling malaria infection; however, the underlying regulatory mechanisms remain largely unknown. This study demonstrated that ATG5 deficiency in myeloid cells can significantly inhibit the growth of rodent blood-stage malarial parasites by selectively enhancing parasite-specific CD4+ Th1 cell responses. This effect was independent of ATG5-mediated canonical and non-canonical autophagy. Mechanistically, ATG5 deficiency suppressed FAS-mediated apoptosis of LY6G- ITGAM/CD11b+ ADGRE1/F4/80- cells and subsequently increased CCL2/MCP-1 production in parasite-infected mice. LY6G- ITGAM+ ADGRE1- cell-derived CCL2 selectively interacted with CCR2 on CD4+ Th1 cells for their optimized responses through the JAK2-STAT4 pathway. The administration of recombinant CCL2 significantly promoted parasite-specific CD4+ Th1 responses and suppressed malaria infection. Conclusively, our study highlights the previously unrecognized role of ATG5 in modulating myeloid cells apoptosis and sequentially affecting CCL2 production, which selectively promotes CD4+ Th1 cell responses. Our findings provide new insights into the development of immune interventions and effective anti-malarial vaccines.Abbreviations: ATG5: autophagy related 5; CBA: cytometric bead array; CCL2/MCP-1: C-C motif chemokine ligand 2; IgG: immunoglobulin G; IL6: interleukin 6; IL10: interleukin 10; IL12: interleukin 12; MFI: mean fluorescence intensity; JAK2: Janus kinase 2; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; pRBCs: parasitized red blood cells; RUBCN: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; STAT4: signal transducer and activator of transcription 4; Th1: T helper 1 cell; Tfh: follicular helper cell; ULK1: unc-51 like kinase 1.

Retraction: Sericin hydrogels promote skin wound healing with effective regeneration of hair follicles and sebaceous glands after complete loss of epidermis and dermis.

Retraction of 'Sericin hydrogels promote skin wound healing with effective regeneration of hair follicles and sebaceous glands after complete loss of epidermis and dermis' by Chao Qi et al., Biomater. Sci., 2018, 6, 2859-2870, https://doi.org/10.1039/C8BM00934A.

LncRNA-targeting bio-scaffold mediates triple immune effects for postoperative colorectal cancer immunotherapy.

Colorectal cancer (CRC) recurrence after surgical resection results in poor clinical outcomes. Long noncoding RNAs (lncRNAs) are emerging new targets for mediating tumorigenesis and immunosuppression within tumor microenvironment. We develop a bio-scaffold encapsulating lncRNA-targeting biomimetic nanosystems for mediating triple immune effects against postoperative CRC recurrence. Liposome (termed as "D")-decorated CRC cells' membrane (CM) envelops a plasmid encoding a short hair-pinned RNA (shRNA) against plasmacytoma variant translocation 1 (Pvt1), forming the shPvt1-CM-D nanosystem. This nanosystem and the chemodrug Oxaliplatin (Oxa) are embedded in a hyaluronic acid and alginate-based bio-scaffold for postoperative implantation. (1) ShPvt1-CM-D-mediated Pvt1 knockdown strengthens Oxa-induced immunogenic cell death (ICD). (2) Such tumor antigens released from enhanced ICD and the CM from shPvt1-CM-D act as dual vaccines of dendritic cells. (3) Pvt1 knockdown by shPvt1-CM-D within granulocytic myeloid-derived suppressor cells (G-MDSCs) ameliorates G-MDSC-mediated immunosuppression. The nanosystem-carrying bio-scaffold significantly suppresses perioperative CRC local recurrence by 97.8% with survival rate (SR) of 62.5%. The bio-scaffold generates robust immune memory responses for completely suppressing tumor ectopic rechallenging and metachronous metastasis (SR: 100%). Additionally, the bio-scaffold reduces synchronously distant metastasis by 70.8%. This work presents a potent nanotechnology-facilitated lncRNA-targeting immunotherapy for postoperative CRC treatments.

RNA profiling of blood platelets noninvasively differentiates colorectal cancer from healthy donors and noncancerous intestinal diseases: a retrospective cohort study.

BACKGROUND: The RNA profiles of tumor-educated platelets (TEPs) possess pathological features that could be used for early cancer detection. However, the utility of TEP RNA profiling in detecting early colorectal cancer (CRC) versus noncancerous colorectal diseases has not yet been investigated. This study assesses the diagnostic capacity of TEP RNA profiles in a cohort of patients with CRC and noncancerous diseases. METHODS: Transcriptome sequencing for platelets isolated from 132 patients with CRC at early and late stages and 190 controls consisting of healthy donors and patients with ulcerative disease, Crohn's disease, polyps, and adenomas was performed and analyzed using binary particle swarm optimization coupled with support vector machine to identify genes that contributed to the classification of CRC patients versus controls. The area under the receiver operating curves (AUROCs) and the accuracy of TEP RNA profiles in CRC diagnosis were assessed. RESULTS: TEP RNA profiling achieved high performance in distinguishing and staging CRC patients from the controls. Using the swarm intelligence algorithm, the 921 most contributive genes that classified CRC patients from the controls were identified. AUROCs of 0.928 for the training set via leave-one-out cross-validation and 0.92 for the validation set were achieved, both of which were significantly higher than the clinically utilized serum biomarkers: carcinoembryonic antigen and cancer antigen 19-9. Notably, an AUROC of 0.915 in an external validation set was achieved. For predicting different CRC stages, an AUROC of 0.984 was achieved in the training set and 1.000 in the internal validation set. CONCLUSIONS: RNA profiles of TEPs are of potential diagnostic value for identifying early CRC from noncancerous diseases. Prospective studies are needed to validate its clinical relevance.

Risk Factors of Anastomotic Leakage After Anterior Resection for Rectal Cancer Patients.

OBJECTIVE: Anastomotic leakage (AL) is one of the serious complications after anterior resection for rectal cancer. Defunctioning stoma (DS) is one of the most widely used approaches to prevent it; however, the effect of DS on the occurrence of AL remains controversial. This study aimed to investigate risk factors of AL and assess the effect of DS after anterior resection for rectal cancer patients. METHODS: A retrospective analysis was conducted for the data of 1840 patients who underwent anterior resection for rectal cancer from January 2014 to December 2019. RESULTS: The results showed the overall AL incidence was 7.5%. Multivariate analyses revealed that males [odds ratio (OR) 1.562] and T3-T4 stage (OR 1.729) were independent risk factors for all patients. After propensity score matching analysis, the AL incidence was 14.1% in the group with no DS and 6.4% in the DS group (P<0.001). The clinical AL (grade B + grade C) incidence was 12.4% in no DS group and 4.6% in the DS group (P<0.001). CONCLUSION: The study suggested that males and T3-T4 stage were independent risk factors of AL. In addition, DS could reduce the rate of symptomatic AL.

Injectable silk sericin scaffolds with programmable shape-memory property and neuro-differentiation-promoting activity for individualized brain repair of severe ischemic stroke.

Severe ischemic stroke damages neuronal tissue, forming irregular-shaped stroke cavities devoid of supporting structure. Implanting biomaterials to provide structural and functional support is thought to favor ingrowth of regenerated neuronal networks. Injectable hydrogels capable of in situ gelation are often utilized for stroke repair, but challenged by incomplete gelation and imprecise control over end-macrostructure. Injectable shape-memory scaffolds might overcome these limitations, but are not explored for stroke repair. Here, we report an injectable, photoluminescent, carbon-nanotubes-doped sericin scaffold (CNTs-SS) with programmable shape-memory property. By adjusting CNTs' concentrations, CNTs-SS' recovery dynamics can be mathematically calculated at the scale of seconds, and its shapes can be pre-designed to precisely match any irregular-shaped cavities. Using a preclinical stroke model, we show that CNTs-SS with the customized shape is successfully injected into the cavity and recovers its pre-designed shape to well fit the cavity. Notably, CNTs-SS' near-infrared photoluminescence enables non-invasive, real-time tracking after in vivo implantation. Moreover, as a cell carrier, CNTs-SS not only deliver bone marrow mesenchymal stem cells (BMSCs) into brain tissues, but also functionally promote their neuronal differentiation. Together, we for the first time demonstrate the feasibility of applying injectable shape-memory scaffolds for stroke repair, paving the way for personalized stroke repair.

A combination of preoperative or intraoperative MB-PDT and surgery in the treatment of giant cutaneous squamous cell carcinoma with infection.

BACKGROUND: Giant cutaneous squamous cell carcinoma (cSCC) with infection is a major clinical issue, as the infection not only promotes the progress of tumor, but also effects the success of surgery. Traditional antibiotic treatment is not always sufficient to clear the infection, especially for cSCC infected with multidrug-resistant bacteria. Photodynamic therapy (PDT) has broad-spectral antibacterial activity and non-selective pressure, which makes it difficult to induce antibiotic resistance. Here, we aim to evaluate the safety and efficacy of PDT, along with photosensitizers MB (Methylene blue) - in the treatment of cSCC infected with multidrug-resistant bacteria. METHODS: In our study, 6 patients with giant csCC accompanied infection were diagnosed by pathological examination and the depth of tumor tissues was examined by X-Ray or MRI. All patients' tumor wounds were firstly irradiated with MB-PDT (635 nm, 120 J/cm2, 100 mW/cm2) using the red LED to control the infection. After the control of infection was confirmed by the culture of secretion, tumor underwent expanded resection. Multi-point pathological monitoring was performed during the operation to assure that there was no residual tumor tissue on the wound, and the primary or secondary repair was performed according to the condition of the wound. If the wound requires the tissue flaps transplation in secondary stage, the wound was irradiated again with intraoperative MB-PDT to remove the possible residual tumor cells, as well as to prevent wound infection. All patients were followed up for 0.8-3 years after flap transplation. RESULTS: In 6 patients, the cSCC infection was completely controlled by MB-PDT, and the flap survival was 100%. There was no recurrence of cSCC in the follow-up of 1.6 years (range, 0.8-3 years) after the comminated treatment with MB-PDT and surgery. CONCLUSIONS: Multi-drug resistant bacteria could efficiently be killed by MB-PDT, and the combination of surgery with MB-PDT is a safe and effective approach for treating giant cSCC with infection.

A sericin/ graphene oxide composite scaffold as a biomimetic extracellular matrix for structural and functional repair of calvarial bone.

Bone defects affect millions of people worldwide each year, leading to severe disabilities. Biomimetic scaffolds mediated tissue regeneration represents a promising alternative for bone repair. However, the major problem associated with most currently clinical available artificial bone substitutes (scaffolds) is that they mainly possess filling function but lack of osteo-induction abilities. Therefore, development of biomaterials with osteo-induction property for effective bone regeneration is highly desired. Methods: We report the design and fabrication of a photo-crosslinked sericin methacryloyl (SerMA)/ graphene oxide (GO) hydrogel (SMH/GO) as a biomimetic scaffold for the functional repair of the bone. The mechanical strength, degradation and biocompatibility behavior of SMH/GO hydrogel were measured in vitro. The effect of SMH/GO hydrogel on BMSCs proliferation, migration, osteogenesis differentiation was assessed. After that, SMH/GO-2 was used as an artificial bone substitute for bone regeneration after calvarial defects and effect on bone repair was evaluated by histological, X-Ray and microCT analysis. Furthermore, the potential mechanism of SMH/GO hydrogel regulating BMSCs migration and differentiation was investigated by RNA sequencing. Results: This scaffold has good biocompatibility, cell adhesive property, proliferation- and migration-promoting effects, and osteogenic induction property. After being implanted in a rat calvarial defect model, this SMH/GO scaffold effectively promotes new bone regeneration and achieves structural and functional repair within 12 weeks by inducing autologous bone marrow-derived mesenchymal stem cells (BMSCs) differentiation. By utilizing cell-biological assays and RNA sequencing, we reveal its possible regeneration mechanisms: the SMH/GO hydrogel regulates BMSCs migration and osteo-differentiation via activating MAPK, TNF, and chemokine signaling for bone regeneration. Conclusion: Aiming to meet clinical demands and overcome current limitations of existing artificial bones, we have developed a new type of sericin/ graphene oxide composite scaffold and provided histological, functional, and molecular evidence demonstrating that it is capable of effectively repairing defective bones by inducing autologous BMSCs directional migration and osteogenic differentiation.

Eosinopenia and elevated C-reactive protein facilitate triage of COVID-19 patients in fever clinic: A retrospective case-control study.

BACKGROUND: Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently a pandemic affecting over 200 countries. Many cities have established designated fever clinics to triage suspected COVID-19 patients from other patients with similar symptoms. However, given the limited availability of the nucleic acid test as well as long waiting time for both the test and radiographic examination, the quarantine or therapeutic decisions for a large number of mixed patients were often not made in time. We aimed to identify simple and quickly available laboratory biomarkers to facilitate effective triage at the fever clinics for sorting suspected COVID-19 patients from those with COVID-19-like symptoms. METHODS: We collected clinical, etiological, and laboratory data of 989 patients who visited the Fever Clinic at Wuhan Union Hospital, Wuhan, China, from Jan 31 to Feb 21. Based on polymerase chain reaction (PCR) nucleic acid testing for SARS-CoV-2 infection, they were divided into two groups: SARS-CoV-2-positive patients as cases and SARS-CoV-2-negative patients as controls. We compared the clinical features and laboratory findings of the two groups, and analyzed the diagnostic performance of several laboratory parameters in predicting SARS-CoV-2 infection and made relevant comparisons to the China diagnosis guideline of having a normal or decreased number of leukocytes (≤9·5 109/L) or lymphopenia (<1·1 109/L). FINDINGS: Normal or decreased number of leukocytes (≤9·5 109/L), lymphopenia (<1·1 109/L), eosinopenia (<0·02 109/L), and elevated hs-CRP (≥4 mg/L) were presented in 95·0%, 52·2%, 74·7% and 86·7% of COVID-19 patients, much higher than 87·2%, 28·8%, 31·3% and 45·2% of the controls, respectively. The eosinopenia produced a sensitivity of 74·7% and specificity of 68·7% for separating the two groups with the area under the curve (AUC) of 0·717. The combination of eosinopenia and elevated hs-CRP yielded a sensitivity of 67·9% and specificity of 78·2% (AUC=0·730). The addition of eosinopenia alone or the combination of eosinopenia and elevated hs-CRP into the guideline-recommended diagnostic parameters for COVID-19 improved the predictive capacity with higher than zero of both net reclassification improvement (NRI) and integrated discrimination improvement (IDI). INTERPRETATION: The combination of eosinopenia and elevated hs-CRP can effectively triage suspected COVID-19 patients from other patients attending the fever clinic with COVID-19-like initial symptoms. This finding would be particularly useful for designing triage strategies in an epidemic region having a large number of patients with COVID-19 and other respiratory diseases while limited medical resources for nucleic acid tests and radiographic examination.

A gold-nanodot-decorated hollow carbon nanosphere based nanoplatform for intracellular miRNA imaging in colorectal cancer cells.

We report a new biofunctionalized nanoplatform based on hyaluronic acid-coated gold-nano-dot-decorated hollow carbon nanospheres (AuHCNs-HA) for microRNA imaging in living cells. Importantly, the HA-coated nanoplatform could be internalized into target cells via CD44 receptor-mediated endocytosis. It can be further applied for intracellular miR-21 imaging in CD44-positive colorectal cancer cells.

Redox-Responsive Dual Drug Delivery Nanosystem Suppresses Cancer Repopulation by Abrogating Doxorubicin-Promoted Cancer Stemness, Metastasis, and Drug Resistance.

Chemotherapy is a major therapeutic option for cancer patients. However, its effectiveness is challenged by chemodrugs' intrinsic pathological interactions with residual cancer cells. While inducing cancer cell death, chemodrugs enhance cancer stemness, invasiveness, and drug resistance of remaining cancer cells through upregulating cyclooxygenase-2/prostaglandin-E2 (COX-2/PGE2) signaling, therefore facilitating cancer repopulation and relapse. Toward tumor eradication, it is necessary to improve chemotherapy by abrogating these chemotherapy-induced effects. Herein, redox-responsive, celecoxib-modified mesoporous silica nanoparticles with poly(ß-cyclodextrin) wrapping (MSCPs) for sealing doxorubicin (DOX) are synthesized. Celecoxib, an FDA-approved COX-2 inhibitor, is employed as a structural and functional element to confer MSCPs with redox-responsiveness and COX-2/PGE2 inhibitory activity. MSCPs efficiently codeliver DOX and celecoxib into the tumor location, minimizing systemic toxicity. Importantly, through blocking chemotherapy-activated COX-2/PGE2 signaling, MSCPs drastically enhance DOX's antitumor activity by suppressing enhancement of cancer stemness and invasiveness as well as drug resistance induced by DOX-based chemotherapy in vitro. This is also remarkably achieved in three preclinical tumor models in vivo. DOX-loaded MSCPs effectively inhibit tumor repopulation by blocking COX-2/PGE2 signaling, which eliminates DOX-induced expansion of cancer stem-like cells, distant metastasis, and acquired drug resistance. Thus, this drug delivery nanosystem is capable of effectively suppressing tumor repopulation and has potential clinical translational value.

Functional extracellular vesicles engineered with lipid-grafted hyaluronic acid effectively reverse cancer drug resistance.

Multidrug resistance (MDR) is a key issue accounting for ineffectiveness of cancer chemotherapy. Numerous multifunctional nanocarriers have been developed to increase drug delivery efficacy and inhibit drug efflux for overcoming cancer drug resistance. However, limited success has been achieved in clinic because of nanocarriers' complicated multi-step fabrication procedures and their undesired side toxicity as well as potential immunogenicity. Here, hyaluronic acid (HA) functionalized extracellular vesicles (EVs) are generated as natural vehicles to efficiently deliver doxorubicin (DOX) and reverse MDR. The EVs isolated from noncancerous HEK293T cells (hEVs) reduce P-glycoprotein (P-gp) expression in drug resistant MCF7/ADR cells. To acquire tumor-targeting capability, hEVs are modified with lipidomimetic chains-grafted HA (lipHA) by a simple incubation. Owing to CD44-mediated cancer-specific targeting and P-gp suppressive capability, the HA-functionalized hEVs (lipHA-hEVs) remarkably promote the intracellular DOX accumulation in drug resistant breast cancer cells. In preclinical MDR tumor models, lipHA-hEVs deeply penetrate into tumor tissue and effectively transport DOX into tumor local, while eliminating DOX's systemic toxicity. Importantly, DOX@lipHA-hEVs inhibited MDR tumor growth by 89% and extend animal survival time by approximately 50%. Thus, our engineered tumor-targeting hEVs are promising natural carriers for overcoming cancer MDR.

Sericin hydrogels promote skin wound healing with effective regeneration of hair follicles and sebaceous glands after complete loss of epidermis and dermis.

Full-thickness skin injury affects millions of people worldwide each year. It often leads to scar formation and loss of skin appendages even after clinical treatment. The majority of wound dressings currently used cannot achieve scarless skin regeneration with complete recovery of appendages such as hair follicles and sebaceous glands. Functional regeneration of these skin appendages is a great challenge. However, we achieved this goal by the successful development and utilization of a photo-crosslinkable sericin hydrogel (SMH) as a new type of wound dressing for repairing full-thickness skin injury. SMH implanted in a mouse full-thickness skin injury model promoted scarless wound healing with effective regeneration of hair follicles and sebaceous glands. By employing techniques of molecular biology, biochemistry, and in vivo cell tracing, we revealed the underlying repair mechanisms: SMH inhibited inflammation, stimulated angiogenesis during healing process, prevented scar tissue formation via regulating the expressions of TGF-ß1 and TGF-ß3, and recruited mesenchymal stem cells to injury sites for regeneration of skin appendages. Collectively, in this study, we developed a sericin-based hydrogel as a wound dressing for full-thickness skin injury repair, uncovered the functional roles of sericin hydrogels in promoting scarless skin regeneration along with effective recovery of skin appendages, and thus unveiled sericin's potential for skin wound healing.

A bioreducible supramolecular nanoparticle gene delivery system based on cyclodextrin-conjugated polyaspartamide and adamantyl-terminated polyethylenimine.

This article describes a novel reduction degradable supramolecular nanoparticle gene delivery system via host-guest interaction based on cyclodextrin-conjugated polyaspartamide with disulfide linkage (Pasp-SS-CD) and adamantyl-terminated polyethylenimine (Ad4-PEI). The reduction responsiveness of Pasp-SS-CD and the Pasp-SS-CD/Ad4-PEI/pDNA supramolecular nanoparticles (SNPs) in the presence of dl-dithiothreitol (DTT) was confirmed by SEC-MALLS and DLS analysis, respectively. Compared with the Ad4-PEI/pDNA polyplexes, the bioreducible supramolecular polycation/pDNA polyplexes exhibited smaller particle size, slightly higher zeta potential, lower cytotoxicity and hemolysis ratio, improved cellular internalization and higher gene transfection efficiency. It was found that introducing Pasp-SS-CD to assemble Ad4-PEI could substantially enhance the tolerance of protein adsorption and maintain the gene transfer capacity of polycationic carriers, which might be beneficial for in vivo use. In addition, the cellular uptake pathway of the supramolecular polycation/pDNA polyplexes was investigated using different uptake inhibitors. The present study demonstrates that the proper assembly of cyclodextrin-conjugated polyaspartamide and adamantyl-terminated polyethylenimine is an effective strategy for the production of a new gene delivery system.