Although many agents have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed.

Nanoparticle (NP) drug loading is one of the key defining characteristics of a NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT®), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel.

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The treatment of aggressive non-small-cell lung cancer (NSCLC) depends on the creation of new therapeutic regimens in clinical settings. In this study, we developed a Lipid/Calcium/Phosphate (LCP) nanoparticle that combines chemotherapy with gene therapy. By encapsulating a chemodrug, gemcitabine monophosphate (GMP), and siRNA specific to the undruggable c-Myc oncogene (c-Myc siRNA) into a single nanosized vesicle and systemically administering them to nude mice, we achieved potent anti-tumor activity in both subcutaneous and orthotopic models of NSCLC. The improvements in therapeutic response over either c-Myc siRNA or GMP therapy alone, were demonstrated by the ability to effectively induce the apoptosis of tumor cells and the significant reduction of proliferation of tumor cells. The combination therapy led to dramatic inhibition of tumor growth, with little in vivo toxicity. Additionally, the current studies demonstrated the possibility of incorporating both nucleic acid molecules and phosphorylated small molecule drugs into the inner core of a single nanoparticle formulation. Co-encapsulation of an oncogene-modulating siRNA and a chemotherapeutic agent will allow simultaneous interruption of diverse anti-cancer pathways, leading to increased therapeutic efficacy and reduced toxicities.

Pathogenic bacteria infection severely threatens human health and causes substantial medical and financial concern. Rapid, sensitive, specific, and reliable detection of pathogenic bacteria is crucial. In the current study, a CRISPR-Cas12a-powered dual-mode biosensor was developed for ultrasensitive and cross-validating detection of pathogenic bacteria. Simply, the amplicons of Salmonella (used as a model)-specific invA sequence triggered CRISPR-Cas12a-based indiscriminate degradation of single-stranded DNAs that were supposed to link two gold nanoparticle (AuNP) probe pairs, inducing an aggregation-to-dispersion change. This generated observable color changes that became even more apparent after centrifugation. The color changes can be discerned by naked eyes and recorded using a portable colorimeter. Meanwhile, the photothermal effect of CRISPR-Cas12-powered AuNPs was explored for the first time through 808 nm near-infrared irradiation such that quantitative measurement can be carried out by recording temperatures using a thermal camera. For both modes, a limit of detection of 1 CFU/mL and a dynamic range of detection from 100 to 108 CFU/mL were obtained, which were comparable with or better than previously reported methods. Our proposed biosensor demonstrated satisfactory selectivity for Salmonella against other interfering cells. Furthermore, this biosensor proved to be capable of Salmonella detection in food samples. Regarding the real applications, the result from each mode can be used for cross-validation. Only the case having doubly confirmed positive or negative results can be assured, which rendered a more dependable biosensing conclusion. This technology not only expands the reach of the CRISPR-Cas system in biosensing but also provides a general method for bacteria sensing with desirable sensitivity, specificity, and cross-validating capacity.