Bisphosphonates loaded nanoparticles in microparticles: a potential macrophage targeting and repolarizing drug delivery system.

Bisphosphonates (BPs) are widely used in treating bone-related conditions, with emerging evidence supporting their potential in treating both skeletal and extra-skeletal diseases. However, their clinical utility is limited by high cytotoxicity, particularly toward macrophages, leading to immune system disruption upon frequent use. This limitation highlights the need for an effective drug delivery system. While nanoparticle formulations improve pharmacokinetics and biodistribution, they often suffer from limited drug loading capacity, poor sustained-release ability, and increased cytotoxicity due to their rapid and excessive intracellular uptake.Here, we present a multifunctional formulation, composed of calcium-zoledronic acid nanoparticles (CaZol NP) encapsulated within polymeric microparticles (CaZol NiM), designed to address many challenges associated with therapeutic use of zoledronic acid (Zol). CaZol NiM improves cellular uptake of Zol, facilitates pH sensitive sustained release of Zol and allows ligand mediated uptake by macrophages. The controlled release of Zol from CaZol NiM effectively reduces Zol's cytotoxic effects on macrophages, enabling their immune modulation by suppressing NF-κB and reactive oxygen species (ROS) activity, while promoting macrophage repolarization from their pro-inflammatory M1 state.Altogether, these findings highlight the potential of CaZol NiM in minimizing off-target effect and expand the clinical applications of Zol in managing both skeletal and extra-skeletal inflammatory disorders.