Dual-Targeted, Stimuli-Responsive PLGA Nanoparticles for Osteoporosis: Co-Functionalization with Bone- and Osteoclast-Specific Ligands Enables Controlled Risedronate Delivery

Osteoporosis is a widespread skeletal disease characterized by low bone mass and microarchitectural deterioration, leading to fragile bones and high fracture risk[1]. Current therapies, such as bisphosphonates and RANKL inhibitors, are effective at reducing bone loss but suffer from poor targeting, low oral bioavailability[2], and significant side effects. We propose a novel nanoparticle-based therapeutic strategy to address these limitations. In this research proposal, a dual-targeted, stimuli-responsive nanoparticle (NP) system is designed for the precision treatment of osteoporosis. The NP consists of a biodegradable poly (lactic-co-glycolic acid) (PLGA) core loaded with the anti-resorptive drug risedronate [3]. The NP is functionalized with two targeting ligands: one ligand confers strong binding to bone mineral (hydroxyapatite), and a second ligand specifically targets osteoclasts or bone resorption sites (e.g. a RANKL-mimetic peptide). Additionally, the NP is coated with a pH-sensitive polymer (such as poly(L-histidine) or a chitosan derivative) that remains stable at physiological pH but triggers drug release in the acidic microenvironment of active bone resorption sites. We hypothesize that this dual-targeted, acid-responsive NP will preferentially deliver risedronate to osteoporotic bone lesions, enhancing local efficacy while minimizing off-target exposure.This proposal outlines the rationale and design of the nanoparticle system, the synthesis and formulation methods, and detailed experimental plans for in vitro and in vivo testing. In vitro studies will evaluate NP characterization, pH-responsive drug release, bone-binding affinity, cellular uptake by osteoclasts, and anti-resorptive efficacy in cell culture. In vivo studies will utilize an ovariectomized osteoporotic rodent model to assess oral bioavailability, biodistribution to bone, therapeutic efficacy in improving bone density and strength, and safety profile compared to free risedronate. We will also include comparisons to single-target or non-responsive nanoparticle variants to demonstrate the advantages of the dual-targeted, stimuli-responsive approach. By integrating dual targeting and stimuli-triggered release, this strategy aims to significantly improve the precision of osteoporosis treatment. The expected outcome is a nanoparticle therapy that achieves higher drug concentration at bone lesions, greater inhibition of bone resorption, and fewer systemic side effects than current treatments. If successful, this research will pave the way for a new class of targeted osteoporosis therapeutics with improved efficacy and patient compliance.