Triple-pathway synergistic senolysis via AKAP1 silencing and calcium overload: An aptamer-functionalized DNAzyme nanoplatform for anti-pulmonary fibrosis research

A triple-pathway synergistic strategy integrating calcium overload, AKAP1 silencing, and caspase-8 activation for senolysis. • L1CAM aptamer-functionalized nanoplatform enables targeted delivery to senescent alveolar epithelial type II cells. • Acid-responsive CaCO 3 core releases curcumin, Mn 2+ , DNAzyme; Mn 2+ acts as cofactor & caspase-8 activator. • Inhalable nanoplatform effectively clears senescent cells, alleviates fibrosis, and restores lung function in vivo . Idiopathic pulmonary fibrosis (IPF) lacks therapies that reverse disease progression, partly due to persistent senescent alveolar epithelial type II cells (SAEC II). We report a synergistic senolytic strategy combining mitochondrial calcium overload with AKAP1 silencing. An acid-responsive nanoplatform (CCMD@Lipo-Apt) comprising a CaCO 3 core co-loaded with curcumin (CUR), Mn 2+ , and an AKAP1-targeting DNAzyme, enveloped by an L1CAM aptamer-modified lipid bilayer, enables SAEC II-specific homing. Upon lysosomal acidification, CaCO 3 degrades to release Ca 2+ , CUR (mobilizing ER Ca 2+ ), Mn 2+ , and the DNAzyme. Mn 2+ simultaneously activates DNAzyme to knockdown AKAP1 (sensitizing mitochondria to calcium overload) and directly activates caspase-8. This triple mechanism collapses mitochondrial membrane potential and triggers robust apoptosis exclusively in SAEC II. In a bleomycin-induced mouse model, CCMD@Lipo-Apt clears SAEC II, attenuates fibrosis, and restores lung function without overt toxicity. This work establishes a synthetic-lethal axis for targeted IPF therapy.