Exosomes are cell-derived nanovesicles that are involved in the intercellular transportation of materials. Therapeutics, such as small molecules or nucleic acid drugs, can be incorporated into exosomes and then delivered to specific types of cells or tissues to realize targeted drug delivery. Targeted delivery increases the local concentration of therapeutics and minimizes side effects. Here, we present a detailed review of exosomes engineering through genetic and chemical methods for targeted drug delivery. Although still in its infancy, exosome-mediated drug delivery boasts low toxicity, low immunogenicity, and high engineerability, and holds promise for cell-free therapies for a wide range of diseases.
Targeted
delivery
to the diseased cell
or tissue is the key to the successful clinical use of nucleic acid
drugs. In particular, delivery of microRNA-140 (miRNA-140, miR-140)
into chondrocytes across the dense, nonvascular extracellular matrix
of cartilage remains a major challenge. Here, we report the chondrocyte-targeting
exosomes as vehicles for the delivery of miR-140 into chondrocytes
as a new treatment for osteoarthritis (OA). By fusing a chondrocyte-affinity
peptide (CAP) with the lysosome-associated membrane glycoprotein 2b
protein on the surface of exosomes, we acquire CAP-exosomes that can
efficiently encapsulate miR-140, specifically enter, and deliver the
cargo into chondrocytes in vitro. CAP-exosomes, in contrast to nontagged
exosome vesicles, are retained in the joints after intra-articular
injection with minimal diffusion in vivo. CAP-exosomes also deliver
miR-140 to deep cartilage regions through the dense mesochondrium,
inhibit cartilage-degrading proteases, and alleviate OA progression
in a rat model, pointing toward a potential organelle-based, cell-free
therapy of OA.
Enzymatic reactions in living cells are highly dynamic but simultaneously tightly regulated. Enzyme engineers seek to construct multienzyme complexes to prevent intermediate diffusion, to improve product yield, and to control the flux of metabolites. Here we choose a pair of short peptide tags (RIAD and RIDD) to create scaffold-free enzyme assemblies to achieve these goals. In vitro, assembling enzymes in the menaquinone biosynthetic pathway through RIAD–RIDD interaction yields protein nanoparticles with varying stoichiometries, sizes, geometries, and catalytic efficiency. In Escherichia coli, assembling the last enzyme of the upstream mevalonate pathway with the first enzyme of the downstream carotenoid pathway leads to the formation of a pathway node, which increases carotenoid production by 5.7 folds. The same strategy results in a 58% increase in lycopene production in engineered Saccharomyces cerevisiae. This work presents a simple strategy to impose metabolic control in biosynthetic microbe factories.
Newer treatments including terbinafine, itraconazole and fluconazole are at least similar to griseofulvin in children with tinea capitis caused by Trichophyton species. Limited evidence suggests that terbinafine, itraconazole and fluconazole have similar effects, whereas ketoconazole may be less effective than griseofulvin in children infected with Trichophyton. With some interventions the proportion achieving complete clinical cure was in excess of 90% (e.g. one study of terbinafine or griseofulvin for Trichophyton infections), but in many of the comparisons tested, the proportion cured was much lower.New evidence from this update suggests that terbinafine is more effective than griseofulvin in children with T. tonsurans infection.However, in children with Microsporum infections, new evidence suggests that the effect of griseofulvin is better than terbinafine. We did not find any evidence to support a difference in terms of adherence between four weeks of terbinafine versus eight weeks of griseofulvin. Not all treatments for tinea capitis are available in paediatric formulations but all have reasonable safety profiles.
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