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Abstract Background Cisplatin (DDP) is an efficacious and widely applied chemotherapeutic drug for cervical cancer patients who are diagnosed as metastatic and inoperable, or desiring fertility preservation. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) selectively triggers cancer cells apoptosis by binding to cognate death receptors (DR4 and DR5). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been regarded as ideal drug carriers on account of their nanoscale, low toxicity, low immunogenicity, high stability, biodegradability, and abundant sources. Methods Human chorion-derived mesenchymal stem cells (hCD-MSCs) were isolated by adherent culture method. TRAIL-engineered hCD-MSCs (hCD-MSCsTRAIL) were constructed by lentivirus transfection, and its secreted Exo (hCD-MSCs-ExoTRAIL) were acquired by differential centrifugation and confirmed to overexpress TRAIL by western blotting. Next, nanoscale drug delivery systems (DDP & hCD-MSCs-ExoTRAIL) were fabricated by loading DDP into hCD-MSCs-ExoTRAIL via electroporation. The CCK-8 assay and flow cytometry were conducted to explore the proliferation and apoptosis of cervical cancer cells (SiHa and HeLa), respectively. Cervical cancer-bearing nude mice were constructed to examine the antitumor activity and biosafety of DDP & hCD-MSCs-ExoTRAIL in vivo. Results Compared with hCD-MSCs-Exo, hCD-MSCs-ExoTRAIL weakened proliferation and enhanced apoptosis of cervical cancer cells. DDP & hCD-MSCs-ExoTRAIL were proved to retard cervical cancer cell proliferation and propel cell apoptosis more effectively than DDP or hCD-MSCs-ExoTRAIL alone in vitro. In cervical cancer-bearing mice, DDP & hCD-MSCs-ExoTRAIL evidently hampered tumor growth, and its role in inducing apoptosis was mechanistically associated with JNK/p-c-Jun activation and survivin suppression. Moreover, DDP & hCD-MSCs-ExoTRAIL showed favorable biosafety in vivo. Conclusions DDP & hCD-MSCs-ExoTRAIL nanoparticles exhibited great promise for cervical cancer treatment as an Exo-based chemo-gene combinational therapy in clinical practice. Graphical abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to pose a significant threat to global health. The resilience of TB is amplified by a myriad of physical, biological, and biopharmaceutical barriers that challenge conventional therapeutic approaches. This review navigates the intricate landscape of TB treatment, from the stealth of latent infections and the strength of granuloma formations to the daunting specters of drug resistance and altered gene expression. Amidst these challenges, traditional therapies often fail, contending with inconsistent bioavailability, prolonged treatment regimens, and socioeconomic burdens. Nanoscale Drug Delivery Systems (NDDSs) emerge as a promising beacon, ready to overcome these barriers, offering better drug targeting and improved patient adherence. Through a critical approach, we evaluate a spectrum of nanosystems and their efficacy against MTB both in vitro and in vivo. This review advocates for the intensification of research in NDDSs, heralding their potential to reshape the contours of global TB treatment strategies.

Background: Cisplatin (DDP) is an efficacious and widely applied chemotherapeutic drug for cervical cancer patients who are diagnosed as metastatic and inoperable, or desiring fertility preservation. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) selectively triggers cancer cells apoptosis by binding to cognate death receptors (DR4 and DR5). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been regarded as ideal drug carriers on account of their nanoscale, low toxicity, low immunogenicity, high stability, biodegradability, and abundant sources. Methods: Human chorion-derived mesenchymal stem cells (hCD-MSCs) were isolated by adherent culture method. TRAIL-engineered hCD-MSCs (hCD-MSCsTRAIL) were constructed by lentivirus transfection, and its secreted Exo (hCD-MSCs-ExoTRAIL) were acquired by differential centrifugation and confirmed to overexpress TRAIL by western blotting. Next, nanoscale drug delivery systems (DDP & hCD-MSCs-ExoTRAIL) were fabricated by loading DDP into hCD-MSCs-ExoTRAIL via electroporation. The CCK-8 assay and flow cytometry were conducted to explore the proliferation and apoptosis of cervical cancer cells (SiHa and HeLa), respectively. Cervical cancer-bearing nude mice were constructed to examine the antitumor activity and biosafety of DDP & hCD-MSCs-ExoTRAIL in vivo. Results: Compared with hCD-MSCs-Exo, hCD-MSCs-ExoTRAIL weakened proliferation and enhanced apoptosis of cervical cancer cells. DDP & hCD-MSCs-ExoTRAIL were proved to retard cervical cancer cell proliferation and propel cell apoptosis more effectively than DDP or hCD-MSCs-ExoTRAIL alone in vitro. In cervical cancer-bearing mice, DDP & hCD-MSCs-ExoTRAIL evidently hampered tumor growth, and its role in inducing apoptosis was mechanistically associated with JNK/p-c-Jun activation and survivin suppression. Moreover, DDP & hCD-MSCs-ExoTRAIL showed favorable biosafety in vivo. Conclusions: DDP & hCD-MSCs-ExoTRAIL nanoparticles exhibited great promise for cervical cancer treatment as an Exo-based chemo-gene combinational therapy in clinical practice. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation. Nevertheless, current therapeutic regimens are inadequate to promptly address the vast diversity of potential pathogens. Omiganan, an antimicrobial peptide, has shown promise for neutralizing endotoxins and eliminating diverse pathogens. However, its clinical application is hindered by safety and stability concerns. Herein, we present a nanoscale drug delivery system (Omi-hyd-Dex@HA NPs) that selectively targets infectious microenvironments (IMEs) and responds to specific stimuli for efficient intervention in sepsis. The system consists of omiganan-dexamethasone conjugates linked by hydrazone bonds which self-assemble into nanoparticles coated with a hyaluronic acid (HA). The HA coating not only facilitates IMEs-targeting through interaction with intercellular-adhesion-molecule-1 on inflamed endotheliocytes, but also improves the biosafety of the nanosystem and enhances drug accumulation in primary infection sites triggered by hyaluronidase. The nanoparticles release dual drugs in IMEs through pH-sensitive cleavage of hydrazone bonds to eradicate pathogens and suppress inflammation. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC), one of the most common and deadliest diseases worldwide, poses a great health threat and social burden. The clinical treatments of CRC encompassing surgery, chemotherapy, and radiotherapy are challenged with toxicity, therapy resistance, and recurrence. In the past two decades, targeted therapy and immunotherapy have greatly improved the therapeutic benefits of CRC patients but they still suffer from drug resistance and low response rates. Very recently, gut microbiota regulation has exhibited a great potential in preventing and treating CRC, as well as in modulating the efficacy and toxicity of chemotherapy and immunotherapy. In this review, we provide a cutting-edge summary of nanomedicine-based treatment in colorectal cancer, highlighting the recent progress of oral and systemic tumor-targeting and/or tumor-activatable drug delivery systems as well as novel therapeutic strategies against CRC, including nano-sensitizing immunotherapy, anti-inflammation, gut microbiota modulation therapy, etc. Finally, the recent endeavors to address therapy resistance, metastasis, and recurrence in CRC were discussed. We hope this review could offer insight into the design and development of nanomedicines for CRC and beyond. [Display omitted] • CRC targeting and activatable nanodrugs with different administration manners are reviewed. • Approaches to enhance nano-sensitizing immunotherapy of CRC are summarized. • Modulation of Inflammation and microbiota and precision therapy emerge as new therapy strategies. • Recent advance of nanodrugs addressing therapy resistance, metastasis and recurrence is provided. [ABSTRACT FROM AUTHOR]

To date, chemotherapy, the main treatment for malignant tumors, still fails to provide ideal therapeutic efficacy, which is deeply rooted in various physiological barriers, either temporal or spatial, to the delivering of anticancer drugs to solid tumor sites during chemotherapy. In the meantime, the therapeutic efficacy of anticancer drugs is affected by inherent cancer characteristics, drug transport, cellular uptake and other complex interactions. Recently, advances have been constantly achieved on nanoscale drug delivery systems (NDDSs) for anticancer drug delivery, driven by their excellent stability and effectiveness in improving water solubility of anticancer drugs, prolonging systemic circulation time, reducing side effects and improving anticancer effects. This paper presents an overview of the current research status and challenges in applying NDDSs to anticancer drug delivery. [ABSTRACT FROM AUTHOR]

Nanoscale drug delivery systems (NDDS) have shown great potential in tumor treatment due to its unique advantages, especially its unique enhanced permeability and retention effect (EPR) in solid tumors. Therefore, NDDS have been extensively explored in recent years. However, current NDDS did not achieve satisfied clinical therapeutic effect against to tumor treatment. This is mainly ascribed to two reasons. One is that nanocarriers would inevitably encounter a series of physiological and pathological barriers in vivo , leading to low drug transport efficiency. The other is that tumor stroma pose a huge obstruction to tumor therapy, nanotherapeutics just focus on the tumor cells themselves are insufficient for complete tumor eradication. Here in this review, we first outlining sequential biological obstacles encountered by nanocarriers from three levels of blood, tumor tissue and tumor cells. Then, we give a detailed discussion of the role of tumor stroma, and highlight the therapeutic resistances mediated by tumor stroma. In light of these formidable barriers, we provide promising approaches to overcome each barrier or remodel stroma through innovative NDDS design. Finally, we give proposals and considerations of NDDS design, and then discuss several existing challenges and further opportunities of NDDS in clinical application. This review seeks to provide guidelines for optimizing NDDS design through mitigation of biological barriers to efficient tumor therapy. [ABSTRACT FROM AUTHOR]

The revolutionary and ubiquitous nature of nanotechnology has fetched it a considerable attention in the past few decades. Even though its enablement and application to various sectors including pharmaceutical drug development is increasing with the enormous government aided funding for nanotechnology-based products, however the parallel commercialization of these systems has not picked up a similar impetus. The technology however does address the unmet needs of pharmaceutical industry, including the reformulation of drugs to improve their solubility, bioavailability or toxicity profiles as observed from the wide array of high-quality research publications appearing in various scientific journals and magazines. Based on our decade-long experience in the field of nanotech-based drug delivery systems and extensive literature survey, we perceive that the major hiccups to the marketing of these nanotechnology products can be categorized as 1) inadequate regulatory framework; 2) lack of support and acceptance by the public, practicing physician, and industry; 3) developmental considerations like scalability, reproducibility, characterization, quality control, and suitable translation; 4) toxicological issues and safety profiles; 5) lack of available multidisciplinary platforms; and, 6) poor intellectual property protection. The present review dwells on these issues elaborating the trends followed by the industry, regulatory role of the USFDA and their implication, and the challenges set forth for a successful translation of these products from the lab and different clinical phases to the market. [ABSTRACT FROM AUTHOR]

Malignant melanoma is an emerging problem worldwide due to the high degree of lethalness. Its aggressiveness and the ability to metastasize along with the heterogeneity at the molecular and cellular levels, limit the overall therapeutic efficacy. Despite significant advances in melanoma treatment over the last decade, there is still a need for improved therapeutic modalities. Thus, we demonstrate here a combinatorial approach that targets multiple independent therapeutic pathways, in which polymeric micelles (PMs) were used as efficacious colloidal nanocarriers loaded with both daunorubicin (DRB) as a cytotoxic drug and IR-768 as a photosensitizer. This afforded the dual drug loaded delivery system IR-768 + DRB in PMs. The fabricated mPEG-b-PLGA micelles (hydrodynamic diameters ≈ 25 nm) had a relatively narrow size distribution (PdI > ca. 0.3) with uniform spherical shapes. CLSM study showed that mPEG-b-PLGA micelles were uptaken by mitochondria, which further contributed to excellent singlet oxygen generation capacity for PDT in A375 melanoma cells. Furthermore, the PMs were efficiently internalized by tested cells through endocytosis, resulting in much higher cellular uptake comparing to the free drug. As a result of these properties, IR-768 + DRB in PMs exhibited very potent and synergistically enhanced anticancer activity against A375 cells. Additionally, this combination approach allowed to reduce drug doses and provided low side effects towards normal HaCaT. This study indicates excellent properties of mPEG-b-PLGA micelles resulting in great therapeutic potential possessed by the developed nanoscale drug delivery system for combined chemo-photodynamic therapy of melanoma. Unlabelled Image • Polymeric micelles co-encapsulating IR-768 and daunorubicin were successfully synthesized • Synergistic effects of chemo and photodynamic therapy increase with the concentration of both drugs • Polymeric micelles were efficiently uptaken by mitochondria • Polymeric micelles exhibited an excellent singlet oxygen generation capacity for PDT in A375 cells [ABSTRACT FROM AUTHOR]