Aptamer-Modified Mesoporous Silica Nanoparticle forNitric Oxide-Enhanced Targeted Sonodynamic Therapy against Lung Cancer

The challenging treatment outcomes for nonsmall cell lung cancer (NSCLC) necessitate the development of innovative therapeutic strategies. In this work, we developed a multifunctional nanoplatform by modifying mesoporous silica nanoparticles (MSNs) with an aptamer (Apt) targeting epidermal growth factor (EFGR), and coloading a sonosensitizer, hematoporphyrin (HP), along with the natural nitric oxide (NO) donor, l-arginine (l-Arg). The resulting Apt-modified MSN loaded with l-Arg and HP (designated as AMLH) was designed for the targeted gas-assisted sonodynamic therapy (SDT) of NSCLC. AMLH exhibited an appropriate particle size, good drug loading ability, and ultrasound-responsive drug release. The coloading of HP and l-Arg resulted in higher encapsulation efficiency compared to single-drug loading, and AMLH remained stable when stored at 4 °C for 15 days. AMLH was capable of generating reactive oxygen species (ROS) and NO under ultrasound stimulation, leading to the further production of peroxynitrite (ONOO^–). AMLH demonstrated specific targeting and recognition of EGFR-positive NSCLC cells, with preincubation of free Apt reducing cellular uptake, confirming the specificity of the Apt-functionalized nanoparticles. Cellular distribution studies revealed that AMLH was primarily localized in lysosomes after internalization. MTT assays and live/dead cell staining confirmed the superior cytotoxicity of AMLH, which effectively inhibits cell proliferation through mitochondrial membrane potential collapse and nuclear damage under ultrasound stimulation. These results highlight the combined efficacy of EGFR targeting, SDT, and NO gas therapy, offering a promising strategy to improve the NSCLC treatment outcomes.