Editors' ChoiceNanomedicine

Some Disassembly Required

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Science Translational Medicine  29 Feb 2012:
Vol. 4, Issue 123, pp. 123ec35
DOI: 10.1126/scitranslmed.3003899

One of the greatest challenges for the clinical development of small interfering RNA (siRNA) therapeutics is overcoming their rapid clearance from the circulation via the kidneys. It would seem logical that formulating siRNAs into nanoparticles larger than the size cutoff for renal filtration (>10 nm) would prevent clearance. Nevertheless, many nanoparticle delivery systems are cleared in minutes, even if they are larger than this cutoff. Now, Davis and colleagues illustrate a surprising new mechanism: The glomerular basement membrane (GBM) disassembles polycation/siRNA complexes, allowing them to cross the renal filtration barrier and be cleared from the circulation.

Davis et al. first injected mice with the siRNA nanoparticles ranging in size from 60 to 100 nm. Using positron emission tomography (PET) imaging, the authors observed that polycation/siRNA nanoparticles between 60 and 100 nm transiently accumulated in the glomerulus of the kidney. By tracking fluorescently labeled siRNA, they could further see that the siRNA nanoparticles localized at the site of the GBM but were cleared within 30 min. Upon further analysis with electron microscopy, the authors found that these particles—held together electrostatically—were visibly disassembled by the GBM, presumably because of the membrane’s high concentration of negatively charged molecules. Mathematical compartment modeling was used to correlate the microscopic observations with the clearance kinetics observed with the PET experiments.

It can now be appreciated that nanoparticles held together with electrostatic interactions are at risk for disassembly and clearance in the kidney, even if they are highly stable in the bloodstream and even if they are larger than the renal filtration size cutoff. Knowledge of this mechanism of clearance can now guide the development of new siRNA delivery strategies: ones that focus on keeping—rather than putting—siRNA nanoparticles together.

J. E. Zuckerman et al., Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane. Proc. Natl. Acad. Sci. U.S.A. 109, 3137–3142 (2012). [Abstract]

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