TPGS‐Functionalized Polydopamine‐Modified Mesoporous Silica as Drug Nanocarriers for Enhanced Lung Cancer Chemotherapy against Multidrug Resistance

A nanocarrier system of d ‐a‐tocopheryl polyethylene glycol 1000 succinate (TPGS)‐functionalized polydopamine‐coated mesoporous silica nanoparticles (NPs) is developed for sustainable and pH‐responsive delivery of doxorubicin (DOX) as a model drug for the treatment of drug‐resistant nonsmall cell lung cancer. Such nanoparticles are of desired particle size, drug loading, and drug release profile. The surface morphology, surface charge, and surface chemical properties are also successfully characterized by a series of techniques such as transmission electron microscopy (TEM), X‐ray photoelectron spectroscopy (XPS), Brunauer‐Emmett‐Teller (BET) method, thermal gravimetric analysis (TGA), dynamic light scattering (DLS), and Fourier transform infrared spectroscopy (FTIR). The normal A549 cells and drug‐resistant A549 cells are employed to access the cytotoxicity and cellular uptake of the NPs. The therapeutic effects of TPGS‐conjugated nanoparticles are evaluated in vitro and in vivo. Compared with free DOX and DOX‐loaded NPs without TPGS ligand modification, MSNs‐DOX@PDA‐TPGS exhibits outstanding capacity to overcome multidrug resistance and shows better in vivo therapeutic efficacy. This splendid drug delivery platform can also be sued to deliver other hydrophilic and hydrophobic drugs.     

Smart Nanosystems for Overcoming Multiple Biological Barriers in Cancer Nanomedicines Transport: Design Principles,Progress, and Challenges

The development of smart nanosystems, which could overcome diverse biological barriers of nanomedicine transport, has received intense scientific interest in improving the therapeutic efficacies of traditional nanomedicines. However, the reported nanosystems generally hold disparate structures and functions, and the knowledge of involved biological barriers is usually scattered. There is an imperative need for a summary of biological barriers and how these smart nanosystems conquer biological barriers, to guide the rational design of the new-generation nanomedicines. This review starts from the discussion of major biological barriers existing in nanomedicine transport, including blood circulation, tumoral accumulation and penetration, cellular uptake, drug release, and response. Design principles and recent progress of smart nanosystems in overcoming the biological barriers are overviewed. The designated physicochemical properties of nanosystems can dictate their functions in biological environments, such as protein absorption inhibition, tumor accumulation, penetration, cellular internalization, endosomal escape, and controlled release, as well as modulation of tumor cells and their resident tumor microenvironment. The challenges facing smart nanosystems on the road heading to clinical approval are discussed, followed by the proposals that could further advance the nanomedicine field. It is expected that this review will provide guidelines for the rational design of the new-generation nanomedicines for clinical use.     

A Tumor‐Specific Cascade Amplification Drug Release Nanoparticle for Overcoming Multidrug Resistance in Cancers

A cascade amplification release nanoparticle (CARN) is constructed by the coencapsulation of β‐lapachone and a reactive‐oxygen‐species (ROS)‐responsive doxorubicin (DOX) prodrug, BDOX, in polymeric nanoparticles. Releasing β‐lapachone first from the CARNs selectively increases the ROS level in cancer cells via NAD(P)H:quinone oxidoreductase‐1 (NQO1) catalysis, which induces the cascade amplification release of DOX and overcomes multidrug resistance (MDR) in cancer cells, producing a remarkably improved therapeutic efficacy against MDR tumors with minimal side effects.     

Subcellular‐Scale Drug Transport via Ultrasound‐Degradable Mesoporous Nanosilicon to Bypass Cancer Drug Resistance

Delivering and releasing anticancer agents directly to their subcellular targets of action in a controlled manner are almost the ultimate goal of pharmacology, but it is challenging. In recent decades, plenty of efforts have been made to send drugs to tumor tissue or even specifically to cancer cells; however, at the subcellular scale, cancer cells have multiple cunning ways to hinder drugs from reaching their final action targets. Here, we demonstrate a strategy to bypass the last defense of cancer drug resistance by contolling the drug transportation and release at subcellular scale. We developed a platform based on ultrasound‐degradable mesoporous nanosilicon, which allows drug delivery towards, ultrasound controlled drug release into the cell nucleus. This strategy altered the drug distribution within cells and remarkably enhanced the drug accumulation ratio at the action target, i.e. nucleus. In vitro and in vivo studies proved that this strategy reduced the drug dosage by an order of magnitude, prolonged drug retention and amplified therapeutic efficacy in tumor‐bearing mice. These results offer new insights into bypassing cancer drug resistance through transport and release drugs directly to their action targets in a controlled manner.     

Metal–Organic Framework (MOF)‐Based Drug/Cargo Delivery and Cancer Therapy

Metal–organic frameworks (MOFs)—an emerging class of hybrid porous materials built from metal ions or clusters bridged by organic linkers—have attracted increasing attention in recent years. The superior properties of MOFs, such as well‐defined pore aperture, tailorable composition and structure, tunable size, versatile functionality, high agent loading, and improved biocompatibility, make them promising candidates as drug delivery hosts. Furthermore, scientists have made remarkable achievements in the field of nanomedical applications of MOFs, owing to their facile synthesis on the nanoscale and alternative functionalization via inclusion and surface chemistry. A brief introduction to the applications of MOFs in controlled drug/cargo delivery and cancer therapy that have been reported in recent years is provided here.     

Magnesium‐Engineered Silica Framework for pH‐Accelerated Biodegradation and DNAzyme‐Triggered Chemotherapy

Inorganic nanocarriers have shown their high performance in disease theranostics in preclinical animal models and further great prospects for clinical translation. However, their dissatisfactory biodegradability and pre‐drug leakage with nonspecificity to lesion sites significantly hinders the possible clinical translation. To solve these two critical issues, a framework‐engineering strategy is introduced to simultaneously achieve enhanced biodegradability and controllable drug releasing, based on the mostly explored mesoporous silica‐based nanosystems. The framework of mesoporous silica is engineered by direct Mg doping via a generic dissolution and regrowth approach, and it can transform into the easy biodegradation of magnesium silicate nanocarriers with simultaneous on‐demand drug release. Such magnesium silicate nanocarriers can respond to the mild acidic environment of tumor tissue, causing the fast breaking up and biodegradation of the silica framework. More interesting, the released Mg²⁺ can further activate Mg²⁺‐dependent DNAzyme on the surface of hollow mesoporous magnesium silicate nanoparticles (HMMSNs) to cleave the RNA‐based gatekeeper, which further accelerates the release of loaded anticancer drugs. Therefore, enhanced anticancer efficiency of chemotherapeutic drugs assisted by the biodegradable intelligent HMMSNs is achieved. The high biocompatibility of nanocarriers and biodegradation products is demonstrated and can be easily excreted via feces and urine guaranteeing their further clinical translation.     

Mesoporous Silica Nanoparticles for Intracellular Controlled Drug Delivery

The application of nanotechnology in the field of drug delivery has attracted much attention in the latest decades. Recent breakthroughs on the morphology control and surface functionalization of inorganic‐based delivery vehicles, such as mesoporous silica nanoparticles (MSNs), have brought new possibilities to this burgeoning area of research. The ability to functionalize the surface of mesoporous‐silica‐based nanocarriers with stimuli‐responsive groups, nanoparticles, polymers, and proteins that work as caps and gatekeepers for controlled release of various cargos is just one of the exciting results reported in the literature that highlights MSNs as a promising platform for various biotechnological and biomedical applications. This review focuses on the most recent progresses in the application of MSNs for intracellular drug delivery. The latest research on the pathways of entry into live mammalian and plant cells together with intracellular trafficking are described. One of the main areas of interest in this field is the development of site‐specific drug delivery vehicles; the contribution of MSNs toward this topic is also summarized. In addition, the current research progress on the biocompatibility of this material in vitro and in vivo is discussed. Finally, the latest breakthroughs for intracellular controlled drug release using stimuli‐responsive mesoporous‐silica‐based systems are described.     

精准纳米气体治疗研究进展

精准纳米气体治疗具有低毒高效等特性, 作为一种新兴的疾病治疗手段受到越来越多的关注。研究表明, 纳米气体治疗不仅能在特定疾病部位选择性杀死癌细胞, 还能保护正常细胞。本文总结了国际最新研究成果, 对精准纳米气体治疗的最新研究进展进行了总结归纳和展望。首先, 阐述了纳米气体治疗的治疗作用和特点; 然后, 总结了实现精准纳米气体治疗的主要途径, 包括靶向气体传输、可控气体释放、医学成像引导和监控气体治疗、基于治疗性气体的多模式联合治疗等; 最后, 对纳米气体治疗存在的问题和发展前景做出了总结和展望。     

ATP Suppression by pH‐Activated Mitochondria‐Targeted Delivery of Nitric Oxide Nanoplatform for Drug Resistance Reversal and Metastasis Inhibition

Mitochondria, which are important mediators for cancer initiation, growth, metastasis, and drug resistance, have been considered as a major target in cancer therapy. Herein, an acid‐activated mitochondria‐targeted drug nanocarrier is constructed for precise delivery of nitric oxide (NO) as an adenosine triphosphate (ATP) suppressor to amplify the therapeutic efficacy in cancer treatments. By combining α‐cyclodextrin (α‐CD) and acid‐cleavable dimethylmaleic anhydride modified PEG conjugated mitochondria‐targeting peptide, the nanocarrier shows prolonged blood circulation time and enhanced cellular uptake together with selectively restoring mitochondria‐targeting capability under tumor extracellular pH (6.5). Such specific mitochondria‐targeted delivery of NO proves crucial in inducing mitochondria dysfunction through facilitating mitochondrial membrane permeabilization and downregulating ATP level, which can inhibit P‐glycoprotein‐related bioactivities and formation of tumor‐derived microvesicles to combat drug resistance and cancer metastasis. Therefore, this pioneering acid‐activated mitochondria‐targeted NO nanocarrier is supposed to be a malignant tumor opponent and may provide insights for diverse NO‐relevant cancer treatments.