Caspase-1-targeting siRNA nanoparticles suppress pyroptosis to prevent force-induced root resorption

Mechanical force-induced hard tissue defects are clinically prevalent, particularly in dentistry. Excessive mechanical stimulation could induce pathological tooth root resorption (RR), which leads to tooth mobility and even tooth loss. This process is closely associated with dysregulated biological alterations in adjacent periodontal ligament stem cells (PDLSCs) and disrupted crosstalk between PDLSCs and osteoclast precursors, yet the specific molecular and cellular mechanisms remain insufficiently understood, severely limiting the development of targeted therapeutic strategies for such hard tissue defects. To address this gap, a mouse model of heavy force-induced RR was established. The results revealed that PDLSC pyroptosis peaked at 14 days after excessive force stimuli and positively correlated with RR severity. Moreover, pyroptosis modulators and Caspase-1 knockout mice were further utilized to confirm the role of Caspase-1-dependent pyroptosis in RR progression. Then, Caspase-1-targeting small interfering RNA (siRNA) nanoparticles (PMSN@siCasp1) was fabricated by modifying mesoporous silica nanoparticles (MSNs) with low-molecular-weight polyethylenimine (PEI), and their RNA loading capacity, lysosomal escape capability and the function of inhibiting excessive-force induced RR were further characterized. PMSN@siCasp1 exhibited excellent biocompatibility and efficient cellular delivery. Additionally, PMSN@siCasp1 was able to penetrate the periodontal ligament and reach the root surface to suppress RR in vivo, with persistent retention on the root surface for an extended period. Mechanically, PMSN@siCasp1 suppressed RR by inhibiting pyroptosis, blocking damaged mitochondrial transfer from PDLSCs to osteoclast precursors, reducing reactive oxygen species (ROS) levels in precursors, and decreasing osteoclast numbers. This study confirms pyroptosis as a key mediator of excessive force-induced RR and presents PMSN@siCasp1 as a promising targeted therapeutic strategy for inhibiting excessive force-induced RR.