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.　©　2025　American　Chemical　Society.