<p>Osteosarcoma is the most common malignant bone tumor in children and adolescents, usually affecting the long bones of the limbs. Despite progress in surgery, chemotherapy, and radiotherapy, patient outcomes remain poor, highlighting the need for better treatments. Nanoparticles have emerged as promising platforms for targeted osteosarcoma therapy, offering selective drug delivery, controlled release, and multifunctional treatment options that improve efficacy and reduce toxicity. Stimulus-responsive nanoparticles further enhance precision by reacting to specific cues in the tumor microenvironment. However, challenges such as biological toxicity, bioaccumulation, stability, and clearance must be addressed. This review summarizes nanoparticle classifications and stimulus-responsive mechanisms in osteosarcoma therapy, discusses current limitations, and highlights future directions, including the development of biodegradable, personalized, and multifunctional nanoparticles and the integration of artificial intelligence to optimize design and accelerate clinical translation.</p>