Nanoparticles Mimicking Viral Cell Recognition Strategies Are Superior Transporters into Mesangial Cells

Abstract

Poor drug availability in the tissue of interest is a frequent cause of therapy failure. While nanotechnology has developed a plethora of nanocarriers for drug transport, their ability to unequivocally identify cells of interest remains moderate. Viruses are the ideal nanosized carriers as they are able to address their embedded nucleic acids with high specificity to their host cells. Here, it is reported that particles endowed with a virus‐like ability to identify cells by three consecutive checks have a superior ability to recognize mesangial cells (MCs) in vivo compared to conventional nanoparticles. Mimicking the initial viral attachment followed by a stepwise target cell recognition process leads to a 5‐ to 15‐fold higher accumulation in the kidney mesangium and extensive cell uptake compared to particles lacking one or both of the viral traits. These results highlight the relevance that the viral cell identification process has on specificity and its application on the targeting strategies of nanomaterials. More so, these findings pave the way for transporting drugs into the mesangium, a tissue that is pivotal in the development of diabetic nephropathy and for which currently no efficient pharmacotherapy exists.

Targeted Delivery of Soluble Guanylate Cyclase (sGC) Activator Cinaciguat to Renal Mesangial Cells via Virus-Mimetic Nanoparticles Potentiates Anti-Fibrotic Effects by cGMP-Mediated Suppression of the TGF-β Pathway

“…COOH-/NH 2 -PEG 2k/5k -PLA 10k block copolymers were synthesized and functionalized with EXP3174/cRGDfK as previously published by our working group [ 39 , 41 , 54 , 55 , 56 ], yielding longer EXP3174-PEG 5k -PLA 10k and shorter cRGD-PEG 2k -PLA 10k . When needed, core component PLGA was additionally coupled to Alexa568 as described before to enable fluorescence imaging of NPs [ 39 ].…”

Biomedical nanoparticle design: What we can learn from viruses

“…Furthermore, we improved the system incorporating an additional viral cell recognition step, the initial cell attachment [ 175 ]. As discussed above, viruses often attach to the host-cell surface to increase the viral concentration and initiate receptor recruitment.…”

“…Control particles with no ligand (NPMeO) or only able to attach (NPEXP) show no glomerular localization. Adapted with permission from [ 175 ]. Copyright 2020, Advanced Science published by Wiley-VCH Verlag & Co. KGaA.…”

“… Stimulus Effect Target NP In vivo Therapy/Cargo Ref. Enzymatic Ligand unveiling MMP-2 PEG-PCL NPs A549 tumor (mouse) Curcumin [ 182 ] MMP-7 PEG NPs – siRNA [ 183 ] MMP-9 PEG Quantum dots BxPC-3 tumor (mouse) GEM [ 184 ] MMP-2 PEG NPs lung tumor (mouse) PTX [ 185 ] “-” PEG Liposomes – – [ 186 ] Legumain Liposomes 4 T1 tumor (mouse) DOX [ 191 ] Ligand activation ACE PEG-PLA/PLGA NPs – – [ 74 , 175 ] Morphology change MMP Peptide NPs HT-1080 tumor (mouse) Pt(II) [ 187 ] MMP-2/9 Peptide/Polymer NPs Myocardial infarct (rat) – [ 188 ] MMP Norbornene/Peptide NPs HT-1080 tumor (mouse) PTX [ 189 ] Bacterial PGA/BLA Polymer NPs – Antibiotics [ 192 ] Bacterial elastase PEI-Pep...…”

“…Enzymes associated with drug-resistant bacterial strains, such as Penicillin G amidase (PGA) and β-lactamase (BLA) [ 192 ] or P. aeruginosa elastase [ 193 ], can also be used as targets to achieve a selective delivery of antimicrobial agents. Lastly, the above-mentioned influenza A mimetic NP concept of our group also depends on an enzymatic cleavage of ligand precursor Ang-I in order to initiate final NP uptake via Ang-II mediated activation of AT1R [ 74 , 175 ]. Enzyme-responsive systems have long been adopted for the controlled delivery of drugs [ 42 , 100 , 184 , 194 ].…”