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广东快乐十分开奖记:Influenza A virus mimetic nanoparticles trigger selective cell uptake
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The identification and targeting of specific cell types are major shortcomings of nanoparticles (NPs) for theragnostic applications. Even in simple cell culture systems, today’s NPs cannot unequivocally distinguish target from off-target cells. To overcome this restraint, we designed NPs that identify cells in an influenza A virus-like manner. Our NPs probe mesangial cells for angiotensin-converting enzyme using angiotensin I (Ang-I) as substrate. The resulting enzymatic reaction transforms Ang-I into Ang-II. Binding of the latter to the Ang-II type-1 receptor (AT1R) confirms the cells’ identity and triggers NP uptake. The particles identified their target cells even with off-target cells present. With cell avidities similar to those of antibodies, the particles are promising transporters for therapeutic and diagnostic applications with pinpoint accuracy.
Poor target cell specificity is currently a major shortcoming of nanoparticles (NPs) used for biomedical applications. It causes significant material loss to off-target sites and poor availability at the intended delivery site. To overcome this limitation, we designed particles that identify cells in a virus-like manner. As a blueprint, we chose a mechanism typical of influenza A virus particles in which ectoenzymatic hemagglutinin activation by target cells is a mandatory prerequisite for binding to a secondary target structure that finally confirms cell identity and allows for uptake of the virus. We developed NPs that probe mesangial cells for the presence of angiotensin-converting enzyme on their surface using angiotensin I (Ang-I) as a proligand. This initial interaction enzymatically transforms Ang-I to a secondary ligand angiotensin II (Ang-II) that has the potential to bind in a second stage to Ang-II type-1 receptor (AT1R). The presence of the receptor confirms the target cell identity and triggers NP uptake via endocytosis. Our virus-mimetic NPs showed outstanding target-cell affinity with picomolar avidities and were able to selectively identify these cells in the presence of 90% off-target cells that carried only the AT1R. Our results demonstrate that the design of virus-mimetic cell interactive NPs is a valuable strategy to enhance NP specificity for therapeutic and diagnostic applications. Our set of primary and secondary targets is particularly suited for the identification of mesangial cells that play a pivotal role in diabetic nephropathy, one of the leading causes of renal failure, for which currently no treatment exists.
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Author contributions: A.G. proposed research; S.M.F., A.V., K.A., D.F., S.B., and A.G. designed research; S.M.F. performed research; S.M.F. analyzed data; S.M.F., A.V., K.A., D.F., S.B., and A.G. discussed results and commented on the manuscript; and S.M.F. and A.G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1902563116/-/DCSupplemental.
Published under the PNAS license.