Nanoparticles hold significant potential for a wide range of clinical applications. Specifically, polymeric drug delivery systems (DDS) have been considered as Stimuli-responsive multifunctional adaptive regulated targeted (SMART) DSS that can deliver the drug at targeted tissue/cells/area or specific site at appropriate time intervals in response to external or internal physiological triggers. Well-defined smart nanoplatforms can enhance the efficacy of targeted drug delivery strategies aimed to reduce the drug’s toxicity, which significantly improves patient compliance. These smart DDS are designed to exhibit a macroscopic alteration in their structure and physical properties in response to specific internal or external physiological stimuli. Fabrication of polymeric nanoparticles and new crosslinkers with improved biodegradability and biocompatibility enables optimal performance within biological systems. The major weakness of these nanoplatforms is the slow response time to external stimuli. The flexibility and combinational synthesis of polymeric nanoparticles allows for precise modulation of their sensitivity to external stimuli. Developing these smart nanoplatforms can lead to achieving precision in targeted drug delivery. This review will focus on recent advancements in smart nanoplatforms for achieving targeted, sustained release of therapeutic molecules and their applications in drug delivery. Furthermore, we highlight the challenges in translating such carriers into clinical studies, future directions and perspectives and AI-optimized stimuli-responsive nano-polymers for next-generation drug delivery systems.