Nanoparticle-based immunotherapeutic strategies to overcome cancer drug resistance: From biological barriers to artificial intelligence-driven design.

Although cancer immunotherapy has revolutionized oncology, its clinical efficacy remains substantially limited by both primary and acquired resistance. These resistance mechanisms are largely driven by complex biological barriers within the tumor microenvironment (TME) and insufficient tumor immunogenicity. Nanotechnology offers a promising strategy to overcome these barriers by enabling precise spatiotemporal control of immune activation. This review provides a comprehensive analysis of emerging nanoparticle-based strategies designed to overcome immunotherapy resistance. Moving beyond conventional drug delivery, we highlight the paradigm shift from empirical engineering to artificial intelligence (AI)-driven design and precision medicine. We critically examine advanced mechanisms for remodeling the hypoxic TME, normalizing tumor vasculature, and reversing immunosuppression by activating the Stimulator of Interferon Genes (STING) pathway and inducing immunogenic cell death (ICD). Furthermore, we discuss integrating AI and machine learning to predict tumor-specific neoantigens and optimize nanocarrier properties, enabling the development of personalized mRNA nanovaccines. Finally, we address key translational challenges-including safety considerations, scalable manufacturing, and regulatory frameworks-that must be addressed to bridge the gap between laboratory innovation and clinical application. Collectively, these advances provide a roadmap for the next generation of smart, mechanism-driven nano-immunotherapeutics capable of transforming immunologically "cold" tumors into "hot" ones.