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Rapamycin slows cystogenesis in murine models of polycystic kidney disease (PKD) but failed in clinical trials, potentially due to insufficient drug dosing. To improve drug efficiency

without increasing dose, kidney-specific drug delivery may be used. Mesoscale nanoparticles (MNP) selectively target the proximal tubules in rodents. We explored whether MNPs can target

cystic kidney tubules and whether rapamycin-encapsulated-MNPs (RapaMNPs) can slow cyst growth in Pkd1 knockout (KO) mice. MNP was intravenously administered in adult Pkd1KO mice. Serum and

organs were harvested after 8, 24, 48 or 72 h to measure MNP localization, mTOR levels, and rapamycin concentration. Pkd1KO mice were then injected bi-weekly for 6 weeks with RapaMNP,

rapamycin, or vehicle to determine drug efficacy on kidney cyst growth. Single MNP injections lead to kidney-preferential accumulation over other organs, specifically in tubules and cysts.

Likewise, one RapaMNP injection resulted in higher drug delivery to the kidney compared to the liver, and displayed sustained mTOR inhibition. Bi-weekly injections with RapaMNP, rapamycin or

vehicle for 6 weeks resulted in inconsistent mTOR inhibition and little change in cyst index, however. MNPs serve as an effective short-term, kidney-specific delivery system, but long-term

RapaMNP failed to slow cyst progression in Pkd1KO mice.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder, with over 50% of patients eventually developing end stage kidney disease. Most ADPKD patients

carry mutations on the PKD1 or PKD2 genes, though kidney cysts appear earlier and progress more rapidly with PKD1 mutations1. Currently, tolvaptan is the only Food and Drug Administration

(FDA) approved drug to treat PKD2,3. However, tolvaptan results in polyuria and constant thirst. It also carries a risk for liver dysfunction, requiring patients to undergo routine bloodwork

for surveillance. A well-known pathway that stimulates proliferation and cystogenesis in ADPKD is the mammalian target of rapamycin (mTOR) pathway4,5. Although mTOR inhibitors sirolimus and

everolimus were shown to slow cyst growth in PKD rodents, they did not slow ADPKD in clinical trials6,7. This may be, in part, a result of dose reduction due to adverse effects, leading to

inadequate kidney mTOR inhibition8,9. To overcome this limitation, and provide a safer, more effective dose, kidney-specific drug delivery could be utilized to circumvent drug metabolism by

the liver.

Nanoparticles (NP), whose bio-distribution is dictated by surface material and size, have recently shown potential applications in diagnostics, imaging, and drug delivery, including cancer

treatment10. FDA-approved poly lactic-co-glycolic acid (PLGA) polymers are physically strong, biocompatible, and biodegradable11. Unsurprisingly, these qualities make PLGA polymers an ideal

surface material for drug-encapsulated NPs. To specifically target the kidney, particles must be large enough not to be quickly cleared from the body upon renal tubule bio-distribution (> 2 

nm)12,13, yet small enough not to accumulate in the liver, spleen14, or lungs15 (