Smart polymeric nanoparticles for targeted delivery and microenvironment-responsive therapy in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies, characterized by aggressive biology, a dense fibrotic and immunosuppressive microenvironment, and profound resistance to standard therapies. Smart polymeric nanoparticles (SPNs), engineered to sense and respond to biological cues, present a transformative approach to overcome these barriers. This review highlights recent advances in SPNs tailored for PDAC, including systems designed to actively target tumor cells, cancer-associated fibroblasts (CAFs), and cancer stem cells (CSCs), thereby enhancing selective drug delivery and efficacy. SPNs also remodel the desmoplastic stroma or deliver matrix-modulating agents to improve tumor penetration. Furthermore, stimuli-responsive SPNs exploit the unique tumor microenvironment (TME) of PDAC, leveraging pH, hypoxia, or enzymatic triggers to achieve controlled, localized drug release. Beyond these strategies, SPNs have been developed to reprogram tumor immunity, modulate metabolic pathways, and enable precision gene therapy or combination treatments. Incorporating chronotherapy principles, future SPNs are capable of synchronizing drug release with circadian rhythms to maximize therapeutic windows while minimizing toxicity. Emerging concepts, such as integrating biosensors for real-time endogenous signal detection or applying AI-driven design to optimize SPN properties, underscore the future potential of these systems. Together, these multifaceted strategies position SPNs as a powerful platform to tackle the formidable challenges of PDAC and advance toward personalized cancer care. \ • Smart polymeric nanoparticles (SPNs) are engineered to target tumor cells, CAFs, and CSCs enhance selective delivery in PDAC, improving therapeutic efficacy. • SPNs can remodel the dense stroma of PDAC by delivering matrix-modulating agents and enhance tumor penetration. • Stimuli-responsive SPNs exploit TME-specific triggers to improve tumor accumulation, penetration, and controlled drug release within PDAC. • SPNs can be used for reprogramming the PDAC tumor immune microenvironment and metabolism, and enabling precision delivery of gene therapies.