Cancer therapy often relies on systemic chemotherapy, which, despite its efficacy, causes significant side effects due to the nonselective targeting of both cancerous and healthy cells. Nanotechnology-based drug delivery systems have been explored to address these issues, offering improved precision and reduced systemic toxicity. However, many nanocarriers face challenges such as limited biocompatibility and insufficient targeting efficiency. To overcome these limitations, targeted drug delivery systems have been developed, employing stimuli-responsive mechanisms and active targeting to enhance therapeutic outcomes while minimizing off-target effects. This study introduces a novel cocklebur-inspired drug delivery system using PAMAM-F127 core–shell nanoparticles functionalized with folic acid for targeted cancer therapy. These nanoparticles also exploit dual stimuli-responsive mechanisms: thermosensitivity derived from the F127 shell and redox sensitivity via disulfide linkages, enabling precise drug release in tumor environments. Characterization using TEM, DLS, FTIR, and 1H NMR confirmed the structural integrity of the system. Biological evaluations demonstrated the biosafety and anticancer efficacy of these nanoparticles. Notably, cellular uptake experiments showed enhanced targeting of folate receptor-overexpressing cancer cells. The findings underline the potential of these dual-responsive nanoparticles in enhancing chemotherapy’s precision and safety, offering a promising pathway for clinical applications in targeted cancer treatment.