Oral Administration Properties Evaluation of Three Milk-Derived Extracellular Vesicles Based on Ultracentrifugation Extraction Methods.

Milk-derived extracellular vesicles (M-EVs) are low-cost, can be prepared in large quantities, and can cross the gastrointestinal barrier for oral administration. However, the composition of milk is complex, and M-EVs obtained by different extraction methods may affect their oral delivery. Based on this, a new method for extracting M-EVs based on cryogenic freezing treatment (Cryo-M-EVs) is proposed and compared with the previously reported acetic acid treatment (Acid-M-EVs) method and the conventional ultracentrifugation method (Ulltr-M-EVs). The new method simplifies the pretreatment step and achieves 25-fold and twofold higher yields than Acid-M-EVs and Ulltr-M-EVs. And it is interesting to note that Cryo-M-EVs and Acid-M-EVs have higher cellular uptake efficiency, and Cryo-M-EVs present the best transepithelial transport effect. After oral administration of the three M-EVs extracted by three methods in mice, Cryo-M-EVs effectively successfully cross the gastrointestinal barrier and achieve hepatic accumulation, whereas Acid-M-EVs and Ultr-M-EVs mostly reside in the intestine. The M-EVs obtained by the three extraction methods show a favorable safety profile at the cellular as well as animal level. Therefore, when M-EVs obtained by different extraction methods are used for oral drug delivery, their accumulation properties at different sites can be utilized to better deal with different diseases.

Immune cell-derived exosomes as promising tools for cancer therapy.

Exosomes are nanoscale vesicles with a size of 30-150 nm secreted by living cells. They are vital players in cellular communication as they can transport proteins, nucleic acids, lipids, and etc. Immune cell-derived exosomes (imEXOs) have great potential for tumor therapy because they have many of the same functions as their parent cells. Especially, imEXOs display unique constitutive characteristics that are directly involved in tumor therapy. Herein, we begin by the biogenesis, preparation, characterization and cargo loading strategies of imEXOs. Next, we focus on therapeutic potentials of imEXOs from different kinds of immune cells against cancer from preclinical and clinical studies. Finally, we discuss advantages of engineered imEXOs and potential risks of imEXOs in cancer treatment. The advantages of engineered imEXOs are highlighted, including selective killing effect, effective tumor targeting, effective lymph node targeting, immune activation and regulation, and good biosafety.

DNA Damage Inducer Mitoxantrone Amplifies Synergistic Mild-Photothermal Chemotherapy for TNBC via Decreasing Heat Shock Protein 70 Expression.

Patients with triple-negative breast cancer (TNBC) have the worst clinical outcomes when compared to other subtypes of breast cancer. Nanotechnology-assisted photothermal therapy (PTT) opens new opportunities for precise cancer treatment. However, thermoresistance caused by PTT, as well as uncertainty in the physiological metabolism of existing phototherapeutic nanoformulations, severely limit their clinical applications. Herein, based on the clinically chemotherapeutic drug mitoxantrone (MTO), a multifunctional nanoplatform (MTO-micelles) is developed to realize mutually synergistic mild-photothermal chemotherapy. MTO with excellent near-infrared absorption (≈669 nm) can function not only as a chemotherapeutic agent but also as a photothermal transduction agent with elevated photothermal conversion efficacy (ƞ = 54.62%). MTO-micelles can accumulate at the tumor site through the enhanced permeability and retention effect. Following local near-infrared irradiation, mild hyperthermia (<50 °C) assists MTO in binding tumor cell DNA, resulting in chemotherapeutic sensitization. In addition, downregulation of heat shock protein 70 (HSP70) expression due to enhanced DNA damage can in turn weaken tumor thermoresistance, boosting the efficacy of mild PTT. Both in vitro and in vivo studies indicate that MTO-micelles possess excellent synergetic tumor inhibition effects. Therefore, the mild-photothermal chemotherapy strategy based on MTO-micelles has a promising prospect in the clinical transformation of TNBC treatment.

Lipid-Based Intelligent Vehicle Capabilitized with Physical and Physiological Activation.

Intelligent drug delivery system based on "stimulus-response" mode emerging a promising perspective in next generation lipid-based nanoparticle. Here, we classify signal sources into physical and physiological stimulation according to their origin. The physical signals include temperature, ultrasound, and electromagnetic wave, while physiological signals involve pH, redox condition, and associated proteins. We first summarize external physical response from three main points about efficiency, particle state, and on-demand release. Afterwards, we describe how to design drug delivery using the physiological environment in vivo and present different current application methods. Lastly, we draw a vision of possible future development.

Functionalized Macrophage Exosomes with Panobinostat and PPM1D-siRNA for Diffuse Intrinsic Pontine Gliomas Therapy.

Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor cell proliferation, and inhibition of PPM1D expression in DIPG cells with PPM1D mutation effectively reduces the proliferation activity of tumor cells. Panobinostat effectively kills DIPG tumor cells, but its systemic toxicity and low blood-brain barrier (BBB) permeability limits its application. In this paper, a nano drug delivery system based on functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for targeted therapy of DIPG with PPM1D mutation is prepared. The nano drug delivery system has higher drug delivery efficiency and better therapeutic effect than free drugs. In vivo and in vitro experimental results show that the nano drug delivery system can deliver panobinostat and siRNA across the BBB and achieve a targeted killing effect of DIPG tumor cells, resulting in the prolonged survival of orthotopic DIPG mice. This study provides new ideas for the delivery of small molecule drugs and gene drugs for DIPG therapy.

High-quality milk exosomes as oral drug delivery system.

Many drugs must be administered intravenously instead of oral administration due to their poor oral bioavailability. The cost of repeated infusion treatment for 6 weeks every year is as high as tens of billions of dollars worldwide. Exosomes are nano-sized (30-150 nm) extracellular vesicles secreted by mammalian cells due to environmental stimulation or self-activation. Milk contains abundant exosomes originated from multiple cellular sources. It has been proved that milk exosomes (MEs) could survive with the strongly acidic conditions in the stomach and degradative conditions in the gut. Furthermore, they can cross biological barriers to reach targeted tissues. The ability of MEs to cross the gastrointestinal barrier makes them as a promising drug delivery tool for oral delivery. This review is devoted to the purification of MEs, their biocompatibility and immunogenicity, and prospects for their use as natural drug carriers for oral administration.

Practicable Applications of Aggregation-Induced Emission with Biomedical Perspective.

Considerable efforts have been made into developing aggregation-induced emission fluorogens (AIEgens)-containing nano-therapeutic systems due to the excellent properties of AIEgens. Compared to other fluorescent molecules, AIEgens have advantages including low background, high signal-to-noise ratio, good sensitivity, and resistance to photobleaching, in addition to being exempt from concentration quenching or aggregation-caused quenching effects. The present review outlines the major developments in the biomedical applications of AIEgens-containing systems. From a literature survey, the recent AIE works are reviewed and the reasons why AIEgens are chosen in various biomedical applications are highlighted. The research activities on AIEgens-containing systems are increasing rapidly, therefore, the present review is timely.