Atopic dermatitis (AD) is a common and relapsing skin disease that is characterized by skin barrier dysfunction, inflammation, and chronic pruritus. While AD was previously thought to occur primarily in children, increasing evidence suggests that AD is more common in adults than previously assumed. Accumulating evidence from experimental, genetic, and clinical studies indicates that AD expression is a precondition for the later development of other atopic diseases, such as asthma, food allergies, and allergic rhinitis. Although the exact mechanisms of the disease pathogenesis remain unclear, it is evident that both cutaneous barrier dysfunction and immune dysregulation are critical etiologies of AD pathology. This review explores recent findings on AD and the possible underlying mechanisms involved in its pathogenesis, which is characterized by dysregulation of immunological and skin barrier integrity and function, supporting the idea that AD is a systemic disease. These findings provide further insights for therapeutic developments aiming to repair the skin barrier and decrease inflammation.

To improve transfection efficiency and reduce the cytotoxicity of polymeric gene vectors, reducible polycations (RPC) were synthesized from low molecular weight (MW) branched polyethyleneimine (bPEI) via thiolation and oxidation. RPC (RPC-bPEI 0.8kDa ) possessed a MW of 5 kDa~80 kDa, and 50%~70% of the original proton buffering capacity of bPEI 0.8kDa was preserved in the final product. The cytotoxicity of RPC-bPEI 0.8kDa was 8~19 times less than that of the gold standard of polymeric transfection reagents, bPEI 25kDa . Although bPEI 0.8kDa exhibited poor gene condensing capacities (~2 µm at a weight ratio (WR) of 40), RPC-bPEI 0.8kDa effectively condensed plasmid DNA (pDNA) at a WR of 2. Moreover, RPC-bPEI 0.8kDa /pDNA (WR ≥ 2) formed 100~200 nm-sized particles with positively charged surfaces (20~35 mV). In addition, the results of the present study indicated that thiol/polyanions triggered the release of pDNA from RPC-bPEI 0.8kDa /pDNA via the fragmentation of RPC-bPEI 0.8kDa and ion-exchange. With negligible polyplex-mediated cytotoxicity, the transfection efficiencies of RPC-bPEI 0.8kDa / pDNA were approximately 1200~1500-fold greater than that of bPEI 0.8kDa /pDNA and were equivalent or superior (~7-fold) to that of bPEI 25kDa /pDNA. Interestingly, the distribution of high MW RPC-bPEI 0.8kDa /pDNA in the nucleus of the cell was higher than that of low MW RPCbPEI 0.8kDa /pDNA. Thus, the results of the present study suggest that RPC-bPEI 0.8kDa has the potential to effectively deliver genetic materials with lower levels of toxicity.

Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.

Polymeric gene carriers are a potential alternative to using viral vectors. Polymeric carriers have relatively low immunogenicity and cytotoxicity. In addition, polymeric carriers can accommodate large-size DNA, be conjugated with appropriate functionalities, and be administered repeatedly. In spite of these advantages, polymeric gene carriers have some limitations, such as low gene transfection efficiencies and relatively short duration of gene expression. Therefore, extensive research has been conducted toward the development of efficient polymeric carriers. In this review, we discuss current problems associated with polymeric gene carriers and various strategies against transfection barriers in particular, gene stabilization and protection, cellular targeting, endosomal escaping, nuclear targeting, unpackaging, and biocompatibility. Finally, requirements for future polymeric gene carriers are considered. With all these ongoing efforts, polymeric carriers have become one of the promising gene delivery methods for human gene therapy.

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