Inhibiting Endothelial Cell-Mediated T Lymphocyte Apoptosis with Integrin-Targeting Peptide-Drug Conjugate Filaments for Chemoimmunotherapy of Triple-Negative Breast Cancer.

Tumor-associated endothelial cells (TECs) limit antitumor immunity via inducing apoptosis of infiltrating T lymphocytes through a Fas ligand (FasL) mediated mechanism. Herein, this work creates a peptide-drug conjugate (PDC) by linking 7-ethyl-10-hydroxycamptothecin (SN38) to hydrophilic segments with either RGDR or HKD motif at their C-terminus through a glutathione-responsive linker. The PDCs spontaneously assemble into filaments in aqueous solution. The PDC filaments containing 1% of SN38-RGDR (SN38-HKD/RGDR) effectively target triple-negative breast cancer (TNBC) cells and TECs with upregulated expression of integrin, and induce immunogenic cell death (ICD) of tumor cells and FasL downregulation of TECs. SN38-HKD/RGDR increases infiltration, activity, and viability of CD8+ T cells, and thus inhibits the growth of primary tumors and pulmonary metastasis. This study highlights the synergistic modulation of cancerous cells and TECs with integrin-targeting PDC filaments as a promising strategy for TNBC chemoimmunotherapy.

STING agonist-boosted mRNA immunization via intelligent design of nanovaccines for enhancing cancer immunotherapy.

Messenger RNA (mRNA) vaccine is revolutionizing the methodology of immunization in cancer. However, mRNA immunization is drastically limited by multistage biological barriers including poor lymphatic transport, rapid clearance, catalytic hydrolysis, insufficient cellular entry and endosome entrapment. Herein, we design a mRNA nanovaccine based on intelligent design to overcome these obstacles. Highly efficient nanovaccines are carried out with machine learning techniques from datasets of various nanocarriers, ensuring successful delivery of mRNA antigen and cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) to targets. It activates stimulator of interferon genes (STING), promotes mRNA-encoded antigen presentation and boosts antitumour immunity in vivo, thus inhibiting tumour growth and ensuring long-term survival of tumour-bearing mice. This work provides a feasible and safe strategy to facilitate STING agonist-synergized mRNA immunization, with great translational potential for enhancing cancer immunotherapy.

Current approaches of nanomedicines in the market and various stage of clinical translation.

Compared with traditional drug therapy, nanomedicines exhibit intriguing biological features to increase therapeutic efficiency, reduce toxicity and achieve targeting delivery. This review provides a snapshot of nanomedicines that have been currently launched or in the clinical trials, which manifests a diversified trend in carrier types, applied indications and mechanisms of action. From the perspective of indications, this article presents an overview of the applications of nanomedicines involving the prevention, diagnosis and treatment of various diseases, which include cancer, infections, blood disorders, cardiovascular diseases, immuno-associated diseases and nervous system diseases, etc. Moreover, the review provides some considerations and perspectives in the research and development of nanomedicines to facilitate their translations in clinic.

Charge-reversal biodegradable MSNs for tumor synergetic chemo/photothermal and visualized therapy.

Given the difficulties of biodegradation of mesoporous silica nanoparticles (NPs), enrichment and penetration of tumor sites, and real-time monitoring of the treatment process, we developed a kind of mannose-doping doxorubicin-loading mesoporous silica nanoparticle (MSN-Man-DOX) and coated by polydopamine-Gd3+ (PDAGd) metal-phenolic networks, as well as modified by poly (2-Ethyl-2-Oxazoline) (PEOz), constructing a novel nanomedicine MSN-Man-DOX@PDA-Gd-PEOz. Its pH-responsive charge reversal, photothermal, biodegradation, drug release, and magnetic resonance imaging (MRI) properties were evaluated in vitro. Cellular uptake, tumor penetration, lysosomal escape properties, as well as cell safety and toxicity of the nanoplatform were investigated through cell experiments. Finally, the MRI, organ distribution, photothermal condition, and comprehensive anti-tumor therapy in vivo were evaluated comprehensively through animal experiments. Research results showed that MSN-Man-DOX@PDA-Gd-PEOz had outstanding tumor enrichment and penetration abilities, which can produce excellent treatment effects through the synergistic effect of chemotherapy and photothermal therapy (PTT) with the function of magnetic resonance imaging contrast agent for disease monitoring. Besides, after finishing the therapeutic effect MSN-Man-DOX@PDA-Gd-PEOz can be biodegraded, so it had a good prospect of clinical application.

Applications of Surface Modification Technologies in Nanomedicine for Deep Tumor Penetration.

The impermeable barrier of solid tumors due to the complexity of their components limits the treatment effect of nanomedicine and hinders its clinical translation. Several methods are available to increase the penetrability of nanomedicine, yet they are too complex to be effective, operational, or practical. Surface modification employs the characteristics of direct contact between multiphase surfaces to achieve the most direct and efficient penetration of solid tumors. Furthermore, their simple operation makes their use feasible. In this review, the latest surface modification strategies for the penetration of nanomedicine into solid tumors are summarized and classified into "bulldozer strategies" and "mouse strategies." Additionally, the evaluation methods, existing problems, and the development prospects of these technologies are discussed.

Insight into potent leads for alzheimer's disease by using several artificial intelligence algorithms.

Several proteins including S-nitrosoglutathione reductase (GSNOR), complement Factor D, complement 3b (C3b) and Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK), have been demonstrated to be involved in pathogenesis pathways for Alzheimer's disease (AD) and considered as potential treatment targets to AD. Based on the concept of multitargets, a network pharmacology-based approach was employed to investigate potential Traditional Chinese Medicine (TCM) candidates that can dock well with GSNOR, C3b, Factor D and PERK proteins. To predict the bioactivities of candidates, Artificial Intelligence (AI) algorithms composed of seven machine learning algorithms and a deep learning model were performed to validate the docking results. Furthermore, in this study, we propose a novel combined method for efficiently exploring the predicted results of AI algorithms. Besides, Comparative force field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) were performed to construct predicted models. The results show that the square correlation coefficients (R2) of all models are almost higher than 0.75, which also acquire good achievements on the test set. Moreover, the binding stability of the potential inhibitors were evaluated using 100 ns of MD simulation. Collectively, this study elucidate that the herbs Ardisia japonica, Ligusticum chuanxiong, Lippia nodiflora and Mirabilis jalapa containing 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), Glyasperin B, Nodifloridin A, Miraxanthin III and l-Valine-l-valine anhydride might be a potential medicine formula for AD.