The role of metabolic reprogramming of oxygen-induced macrophages in the dynamic changes of atherosclerotic plaques.

Atherosclerosis (As) is a chronic vascular inflammatory disease. Macrophages are the most important immune cells in atherosclerotic plaques, and the phenotype of plaque macrophages shifts dynamically to adapt to changes in the plaque microenvironment. The aerobic microenvironment of early atherosclerotic plaques promotes the transformation of M2/alternatively activated macrophages mainly through oxidative phosphorylation; the anoxic microenvironment of advanced atherosclerotic plaques mainly promotes the formation of M1/classically activated macrophages through anaerobic glycolysis; and the adventitia angiogenesis of aged atherosclerotic plaques leads to an increase in the proportion of M2/M1 macrophages. Therefore, this review deeply elucidates the dynamic change mechanism of plaque macrophages and the regulation of plaque oxygen content and immune metabolism to find new targets for the treatment of As.

SMYD3 associates with the NuRD (MTA1/2) complex to regulate transcription and promote proliferation and invasiveness in hepatocellular carcinoma cells.

BACKGROUND: SMYD3, a member of the SET and MYND domain-containing (SMYD) family, is a histone methyltransferase (HMT) and transcription factor that plays an important role in transcriptional regulation in human carcinogenesis. RESULTS: Using affinity purification and mass spectrometry assays to identify SMYD3-associated proteins in hepatocellular carcinoma (HCC) cells, we found several previously undiscovered SMYD3-interacting proteins, including the NuRD (MTA1/2) complex, the METTL family, and the CRL4B complex. Transcriptomic analysis of the consequences of knocking down SMYD3, MTA1, or MTA2 in HCC cells showed that SMYD3/NuRD complex targets a cohort of genes, some of which are critically involved in cell growth and migration. qChIP analyses showed that SMYD3 knockdown led to a significant reduction in the binding of MTA1 or MTA2 to the promoters of IGFBP4 and led to a significant decrease in H4K20me3 and a marked increase in H4Ac at the IGFBP4 promoter. In addition, we demonstrated that SMYD3 promotes cell proliferation, invasion, and tumorigenesis in vivo and in vitro and found that its expression is markedly upregulated in human liver cancer. Knockdown of MTA1 or MTA2 had the same effect as knockdown of SMYD3 on proliferation and invasion of hepatocellular carcinoma cells. Catalytic mutant SMYD3 could not rescue the phenotypic effects caused by knockdown of SMYD3. Inhibitors of SMYD3 effectively inhibited the proliferation and invasiveness of HCC cells. CONCLUSIONS: These findings revealed that SMYD3 could transcriptionally repress a cohort of target genes expression by associating with the NuRD (MTA1/2) complex, thereby promoting the proliferation and invasiveness of HCC cells. Our results support the case for pursuing SMYD3 as a practical prognostic marker or therapeutic target against HCC.

Piperlongumine synergistically enhances the antitumour activity of sorafenib by mediating ROS-AMPK activation and targeting CPSF7 in liver cancer.

Sorafenib, a multikinase inhibitor, is the first-line agent for advanced liver cancer. Sorafenib strongly inhibits both cell proliferation and tumour angiogenesis. However, the development of drug resistance hampers its anticancer efficacy. To improve the antitumour activity of sorafenib, we demonstrate that piperlongumine (PL), an alkaloid isolated from the fruits and roots of Piper longum L., enhances the cytotoxicity of sorafenib in HCCLM3 and SMMC7721 cells using the cell counting kit-8 test. Flow cytometry analysis indicated that PL and sorafenib cotreatment induced robust reactive oxygen species (ROS) generation and mitochondrial dysfunction, thereby increasing the number of apoptotic cells and the ratio of G2/M phase cells in both HCCLM3 and SMMC7721 cells. Furthermore, AMP-protein kinase (AMPK) signalling was activated by excess ROS accumulation and mediated growth inhibition in response to PL and sorafenib cotreatment. RNA-sequencing analysis indicated that PL treatment disrupted RNA processing in HCCLM3 cells. In particular, PL treatment decreased the expression of cleavage and polyadenylation specificity factor 7 (CPSF7), a subunit of cleavage factor I, in a time- and concentration-dependent manner in HCCLM3 and SMMC7721 cells. CPSF7 knockdown using a gene interference strategy promoted growth inhibition of PL or sorafenib monotherapy, whereas CPSF7 overexpression alleviated the cytotoxicity of sorafenib in cultured liver cancer cells. Finally, PL and sorafenib coadministration significantly reduced the weight and volume of HCCLM3 cell xenografts in vivo. Taken together, our data indicate that PL displays potential synergistic antitumour activity in combination with sorafenib in liver cancer.

Homogenous multifunctional microspheres induce ferroptosis to promote the anti-hepatocarcinoma effect of chemoembolization.

Transcatheter arterial chemoembolization (TACE) is one of the main palliative therapies for advanced hepatocellular carcinoma (HCC), which is also regarded as a promising therapeutic strategy for cancer treatment. However, drug-loaded microspheres (DLMs), as commonly used clinical chemoembolization drugs, still have the problems of uneven particle size and unstable therapeutic efficacy. Herein, gelatin was used as the wall material of the microspheres, and homogenous gelatin microspheres co-loaded with adriamycin and Fe3O4 nanoparticles (ADM/Fe3O4-MS) were further prepared by a high-voltage electrospray technology. The introduction of Fe3O4 nanoparticles into DLMs not only provided excellent T2-weighted magnetic resonance imaging (MRI) properties, but also improved the anti-tumor effectiveness under microwave-induced hyperthermia. The results showed that ADM/Fe3O4-MS plus microwave irradiation had significantly better antitumor efficacy than the other types of microspheres at both cell and animal levels. Our study further confirmed that ferroptosis was involved in the anti-tumor process of ADM/Fe3O4-MS plus microwave irradiation, and ferroptosis marker GPX4 was significantly decreased and ACSL4 was significantly increased, and ferroptosis inhibitors could reverse the tumor cell killing effect caused by ADM/Fe3O4-MS to a certain extent. Our results confirmed that microwave mediated hyperthermia could amplify the antitumor efficacy of ADM/Fe3O4-MS by activating ferroptosis and the introduction of Fe3O4 nanoparticles can significantly improve TACE for HCC. This study confirmed that it was feasible to use uniform-sized gelatin microspheres co-loaded with Fe3O4 nanoparticles and adriamycin to enhance the efficacy of TACE for HCC.

Prediction of tumor response via a pretreatment MRI radiomics-based nomogram in HCC treated with TACE.

OBJECTIVES: To develop and validate a pre-transcatheter arterial chemoembolization (TACE) MRI-based radiomics model for predicting tumor response in intermediate-advanced hepatocellular carcinoma (HCC) patients. MATERIALS: Ninety-nine intermediate-advanced HCC patients (69 for training, 30 for validation) treated with TACE were enrolled. MRI examinations were performed before TACE, and the efficacy was evaluated according to the mRECIST criterion 3 months after TACE. A total of 396 radiomics features were extracted from T2-weighted pre-TACE images, and least absolute shrinkage and selection operator (LASSO) regression was applied to feature selection and model construction. The performance of the model was evaluated by receiver operating characteristic (ROC) curves, calibration curves, and decision curves. RESULTS: The AFP value, Child-Pugh score, and BCLC stage showed a significant difference between the TACE response (TR) and non-TACE response (nTR) patients. Six radiomics features were selected by LASSO and the radiomics score (Rad-score) was calculated as the sum of each feature multiplied by the non-zero coefficient from LASSO. The AUCs of the ROC curve based on Rad-score were 0.812 and 0.866 in the training and validation cohorts, respectively. To improve the diagnostic efficiency, the Rad-score was further integrated with the above clinical indicators to form a novel predictive nomogram. Results suggested that the AUC increased to 0.861 and 0.884 in the training and validation cohorts, respectively. Decision curve analysis showed that the radiomics nomogram was clinically useful. CONCLUSION: The radiomics and clinical indicator-based predictive nomogram can well predict TR in intermediate-advanced HCC and can further be applied for auxiliary diagnosis of clinical prognosis. KEY POINTS: • The therapeutic outcome of TACE varies greatly even for patients with the same clinicopathologic features. • Radiomics showed excellent performance in predicting the TACE response. • Decision curves demonstrated that the novel predictive model based on the radiomics signature and clinical indicators has great clinical utility.

Recent advances in near-infrared II imaging technology for biological detection.

Molecular imaging technology enables us to observe the physiological or pathological processes in living tissue at the molecular level to accurately diagnose diseases at an early stage. Optical imaging can be employed to achieve the dynamic monitoring of tissue and pathological processes and has promising applications in biomedicine. The traditional first near-infrared (NIR-I) window (NIR-I, range from 700 to 900 nm) imaging technique has been available for more than two decades and has been extensively utilized in clinical diagnosis, treatment and scientific research. Compared with NIR-I, the second NIR window optical imaging (NIR-II, range from 1000 to 1700 nm) technology has low autofluorescence, a high signal-to-noise ratio, a high tissue penetration depth and a large Stokes shift. Recently, this technology has attracted significant attention and has also become a heavily researched topic in biomedicine. In this study, the optical characteristics of different fluorescence nanoprobes and the latest reports regarding the application of NIR-II nanoprobes in different biological tissues will be described. Furthermore, the existing problems and future application perspectives of NIR-II optical imaging probes will also be discussed.

Sialic acid-engineered mesoporous polydopamine dual loaded with ferritin gene and SPIO for achieving endogenous and exogenous synergistic T2-weighted magnetic resonance imaging of HCC.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. Magnetic resonance imaging (MRI) is one of the most effective imaging methods for the early diagnosis of HCC. However, the current MR contrast agents are still facing challenges in the early diagnosis of HCC due to their relatively low sensitivity and biosafety. Thus, the development of effective MR agents is highly needed for the early diagnosis of HCC. RESULTS: Herein, we fabricated an HCC-targeted nanocomplexes containing SPIO-loaded mesoporous polydopamine (MPDA@SPIO), sialic acid (SA)-modified polyethyleneimine (SA-PEI), and alpha-fetoprotein regulated ferritin gene (AFP-Fth) which was developed for the early diagnosis of HCC. It was found that the prepared nanocomplexes (MPDA@SPIO/SA-PEI/AFP-Fth) has an excellent biocompatibility towards the liver cells. In vivo and in vivo studies revealed that the transfection of AFP-Fth gene in hepatic cells significantly upregulated the expression level of ferritin, thereby resulting in an enhanced contrast on T2-weighted images via the formed endogenous MR contrast. CONCLUSIONS: The results suggested that MPDA@SPIO/SA-PEI/AFP-Fth had a superior ability to enhance the MR contrast of T2-weighted images of tumor region than the other preparations, which was due to its HCC-targeted ability and the combined T2 contrast effect of endogenous ferritin and exogenous SPIO. Our study proved that MPDA@SPIO/SA-PEI/AFP-Fth nanocomplexes could be used as an effective MR contrast agent to detect HCC in the early stage.

Fucoidan-based micelles as P-selectin targeted carriers for synergistic treatment of acute kidney injury.

Acute kidney injury (AKI) is a life-threatening disease without effective treatment. The utilization of curcumin (Cur) for the treatment of AKI is still facing challenges due to its poor water-solubility and low bioavailability. Herein, kidney-targeted octenyl succinic anhydride-grafted fucoidan loaded with Cur (OSA-Fucoidan/Cur) was fabricated for synergistic treatment of AKI. It was found that OSA-Fucoidan/Cur micelles had a sustained drug release behavior and excellent physicochemical stability. Cellular uptake studies demonstrated that the specific binding between fucoidan and P-selectin overexpressed on H2O2-stimulated HUVECs contributed to the higher internalization of OSA-Fucoidan/Cur micelles by the cells. In addition, OSA-Fucoidan micelles exhibited an ideal kidney-targeted characteristic in lipopolysaccharide (LPS)-induced AKI mice. In vivo studies showed that the combination of Cur and OSA-Fucoidan endowed the OSA-Fucoidan/Cur micelles with synergistically anti-inflammatory and antioxidant abilities, thereby largely enhancing the therapeutic efficacy of AKI. Therefore, OSA-Fucoidan/Cur micelles may represent a potential kidney-targeted nanomedicine for effective treatment of AKI.

Flexible liposomal gel dual-loaded with all-trans retinoic acid and betamethasone for enhanced therapeutic efficiency of psoriasis.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease without effective treatment. The utilization of all trans-retinoic acid (TRA) and betamethasone (BT) for the treatment of psoriasis is still facing difficulties, due to their relatively poor stability, limited skin permeation, and systemic side effects. Flexible liposomes are excellent in deeper skin permeation and reducing the side effects of drugs, which is promising for effective treatment of skin disorders. This work aimed to establish dual-loaded flexible liposomal gel for enhanced therapeutic efficiency of psoriasis based on TRA and BT. RESULTS: Flexible liposomes co-loaded with TRA and BT were successfully prepared in our study. The characterization examination revealed that flexible liposomes featured nano-sized particles (around 70 nm), high drug encapsulation efficiency (> 98%) and sustained drug release behaviors. Flexible liposomes remarkably increased the drug skin permeation and retention as compared with free drugs. Results on HaCaT cells suggested that flexible liposomes were nontoxic, and its cellular uptake has a time-dependent manner. In vivo studies suggested the topical application of TRA and BT dual-loaded liposomal gel had the best ability to reduce the thickness of epidermal and the level of cytokines (TNF-α and IL-6), largely alleviating the symptoms of psoriasis. CONCLUSIONS: Flexible liposomal gel dual-loaded with TRA and BT exerted a synergistic effect, which is a promising topical therapeutic for the treatment of psoriasis.

pH and Thermal Dual-Sensitive Nanoparticle-Mediated Synergistic Antitumor Effect of Immunotherapy and Microwave Thermotherapy.

Cationic anticancer peptides, which can induce tumor cell immunogenic death and further promote systemic tumor-specific immune responses, have offered a promising solution to relieve the tumor immunosuppressive microenvironment. However, peptide drugs are easily degraded and lack of targeting ability when administered systemically, leading to limitations in their applications. Herein, we report a pH and thermal dual-sensitive bovine lactoferricin-loaded (one of the most widely studied cationic anticancer peptides) nanoparticles, which simultaneously exhibited antitumor and immune cell activated effects when applied with microwave thermotherapy, an auxiliary method of immunotherapy. The bovine lactoferricin could be delivered to the tumor site by nanoparticles, be immediately released from nanoparticles in the acidic environment of lysosomes and the thermal condition caused by microwave radiation, and ultimately induce tumor apoptosis with the release of damage-associated molecular patterns (DAMPs). It is worth noting that the strategy of bovine lactoferricin-loaded nanoparticles intravenous injection combined with local microwave thermotherapy not only showed excellent efficacy in relieving tumor growth but also resulted in strong antitumor immunities, which was due to the released bovine lactoferricin under stimulating conditions, and the pool of tumor-associated antigens generated by tumor destruction. In conclusion, this work presents a strategy for tumor treatment based on dual-sensitive bovine lactoferricin-loaded nanoparticles combined with microwave thermotherapy, which may provide a solution for cationic anticancer peptides delivery and improving antitumor immune responses.

Polysialic-Acid-Based Micelles Promote Neural Regeneration in Spinal Cord Injury Therapy.

Spinal cord injury (SCI) routinely causes the immediate loss and disruption of neurons followed by complicated secondary injuries, including inflammation, oxidative stress, and dense glial scar formation. Inhibitory factors in the lesion scar and poor intrinsic neural regeneration capacity restrict functional recovery after injury. Minocycline, which has neuroprotective activity, can alleviate secondary injury, but the long-term administration of this drug may cause toxicity. Polysialic acid (PSA) is a large cell-surface carbohydrate that is critical for central nervous system development and is capable of promoting precursor cell migration, axon path finding, and synaptic remodeling; thus, PSA plays a vital role in tissue repair and regeneration. Here, we developed a PSA-based minocycline-loaded nanodrug delivery system (PSM) for the synergistic therapy of spinal cord injury. The prepared PSM exerted marked anti-inflammatory and neuroprotective activities both in vitro and in vivo. The administration of PSM could significantly protect neurons and myelin sheaths from damage, reduce the formation of glial scar, recruit endogenous neural stem cells to the lesion site, and promote the regeneration of neurons and the extension of long axons throughout the glial scar, thereby largely improving the locomotor function of SCI rats and exerting a superior therapeutic effect. The findings might provide a novel strategy for SCI synergistic therapy and the utilization of PSA in other central nervous system diseases.

Tofacitinib citrate-based liposomes for effective treatment of rheumatoid arthritis.

Low drug concentrations at interest sites and unwanted systemic side effects are major obstacles to effective therapy of rheumatoid arthritis (RA). With the aim of improving the efficacy of tofacitinib citrate (TOF), a liposomal system was developed for targeted delivery to inflamed joints, and this approach was validated in a RA rat model. TOF was effectively loaded into the liposomes (entrapment efficiency: 86.5±1.9%; drug loading: 2.3±0.05%) by a pH gradient method, and these molecules featured sustained drug release behaviour over 48 h. In vitro and in vivo studies showed that TOF loaded liposomes (TOFL) could be selectively taken up by inflamed cells and showed improved accumulation in arthritic paws, demonstrating the superior target ability to RA tissues. Moreover, compared to free TOF, TOFL significantly improved the therapeutic efficacy, reduced the inflammatory cytokine expression and lipid peroxidation in synovial cells in the joint tissue of RA rats. Overall, these results indicate that TOFL served as the useful nanocarriers for RA-targeted therapy.

Highly Integrated Nanoplatform Based on an E-Selectin-Targeting Strategy for Metastatic Breast Cancer Treatment.

Therapeutic goals for metastatic breast cancer, including shrinkage of established metastasis and suppression of movement of tumor cells, are often hard to achieve and remain the main obstacles restricting the antimetastatic efficacy of targeted drug delivery systems (TDDSs). Herein, we proposed an E-selectin-targeting nanoplatform for the systemic treatment of metastatic breast cancer. Versatile functions, including killing the circulating tumor cells, shrinking the established lesions, as well as inhibiting the movement of tumor cells, were integrated into doxorubicin-loaded sialic acid-dextran-octadecanoic acid (SDO) micelles (SDD). The prepared SDD micelles could not only inhibit lung and liver metastasis in the orthotopic 4T1 tumors model, but also decrease the metastatic lesions in the metastatic 4T1 cell model, resulting in 27.33% reduced number of metastatic nodules when compared to those without sialic acid modification. It was found that the good antimetastatic effect of SDD was only partially attributed to its ability on removing metastatic cells and metastases. Most importantly, the blank SDO micelles left in the lesion could further inhibit the cell migration and cell-cell binding. These results suggest that SA-driven TDDS has the potential for specific targeting and effective treatment of cancer metastasis.

Acidic/hypoxia dual-alleviated nanoregulators for enhanced treatment of tumor chemo-immunotherapy.

Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.

Multiple Immunomodulatory Strategies Based on Targeted Regulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Immune Homeostasis against Hepatocellular Carcinoma.

Immunotherapy is the most promising systemic therapy for hepatocellular carcinoma. However, the outcome remains poor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in altering cell-surface protein levels, potentially undermining the efficacy of immunotherapy against tumors. This highlights its potential as a target for antitumor therapy. Herein, CaCO3-based nanoparticles coencapsulated with DOX, an immunogenic cell death (ICD) inducer, and evolocumab was developed to enhanced the efficacy of immunotherapy. The obtained DOX/evolocumab-loaded CaCO3 nanoparticle (named DECP) exhibits a good capacity of acid neutralization and causes ICD of cancer cells. In addition, DECP is able to evaluate the cell-surface level of MHC-I, a biomarker that correlates positively with patients' overall survival. Upon intravenous injection, DECP accumulates within the tumor site, leading to growth inhibition of hepa1-6 bearing subcutaneous tumors. Specifically, DECP treatment causes augmented ratios of matured dendritic cells, tumor-infiltrating CD8+ T cells and natural killing cells, while concurrently depleting Foxp3+ regulatory T cells. Peritumoral delivery of DECP enhances the immune response of distant tumors and exhibits antitumor effects when combined with intravenous αPD-L1 therapy in a bilateral tumor model. This study presents CaCO3-based nanoparticles with multiple immunomodulatory strategies against hepatocellular carcinoma by targeting PCSK9 inhibition and modulating immune homeostasis in the unfavorable TME.

Biomaterials evolution: from inert to instructive.

The field of biomaterials has experienced substantial evolution in recent years, driven by advancements in materials science and engineering. This has led to an expansion of the biomaterials definition to include biocompatibility, bioactivity, bioderived materials, and biological tissues. Consequently, the intended performance of biomaterials has shifted from a passive role wherein a biomaterial is merely accepted by the body to an active role wherein a biomaterial instructs its biological environment. In the future, the integration of bioinspired designs and dynamic behavior into fabrication technologies will revolutionize the field of biomaterials. This perspective presents the recent advances in the evolution of biomaterials in fabrication technologies and provides a brief insight into smart biomaterials.

Inactivation of KDM5A suppresses growth and enhances chemosensitivity in liver cancer by modulating ROCK1/PTEN/AKT pathway.

Liver cancer is a kind of malignant tumor with poor sensitivity to chemotherapy. It is urgent to investigate approaches to improve the outcome of chemotherapy. KDM5A has been reported to be an oncogene in various cancers and is associated with drug resistance. However, the functions of KDM5A in chemotherapeutic sensitivity of liver cancer not been well illustrated. In this study, we found that KDM5A was upregulated in liver cancer tissue and cell lines. KDM5A knockdown using a gene interference strategy suppressed the growth of liver cancer in vitro and in vivo. CPI-455, a pharmacological inactivation of KDM5A enhanced the cytotoxicity of cisplatin (CDDP) in liver cells. CPI-455 and CDDP cotreatment resulted in apoptosis and mitochondrial dysfunction. We also found that knockdown or inactivation of KDM5A resulted in the downregulation of ROCK1, an oncogene regulating the activation of the PTEN/AKT signaling pathway. In particular, overexpression of ROCK1 or SF1670, a pharmacological inhibitor of PTEN, alleviated the cytotoxicity of CPI-455 and CDDP cotreatment. In HCCLM3 xenografts, CPI-455 and CDDP cotreatment dramatically inhibited the growth of xenograft tumor compared to CPI-455 or CDDP treatment alone. In conclusion, this study suggested that targeting the inactivation of KDM5A is an efficient strategy to enhance the chemosensitivity of liver cancer cells to CDDP by modulating the ROCK1/PTEN/AKT signaling pathway.

Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges.

Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks.

Monodisperse CaCO3-loaded gelatin microspheres for reversing lactic acid-induced chemotherapy resistance during TACE treatment.

Transarterial chemoembolization (TACE) is an important approach for the treatment of unresectable hepatocellular carcinoma (HCC). However, the lactic acid-induced acidic tumor microenvironment (TME) may reduce the therapeutic outcome of TACE. Herein, monodispersed gelatin microspheres loaded with calcium carbonate nanoparticles (CaNPs@Gel-MS) as novel embolic agents were prepared by a simplified microfluidic device. It was found that the particle size and homogeneity of as-prepared CaNPs@Gel-MS were strongly dependent on the flow rates of continuous and dispersed phases, and the inner diameter of syringe needle. The introduction of CaNPs provided the gelatin microspheres with an enhanced ability to encapsulate the chemotherapeutic drug of DOX, as well as a pH-responsive sustained drug release behavior. In vitro results revealed that CaNPs@Gel-MS could largely increase the cellular uptake and chemotoxicity of DOX by neutralizing the lactic acid in the culture medium. In addition, CaNPs@Gel-MS exhibited an excellent and persistent embolic efficiency in a rabbit renal model. Finally, we found that TACE treatment with DOX-loaded CaNPs@Gel-MS (DOX/CaNPs@Gel-MS) had a much stronger ability to inhibit tumor growth than the DOX-loaded gelatin microspheres without CaNPs (DOX@Gel-MS). Overall, CaNPs@Gel-MS could be a promising embolic microsphere that can significantly improve anti-HCC ability by reversing lactic acid-induced chemotherapy resistance during TACE treatment.