All-In-One Gadolinium–Doxorubicin Nanoassemblies for Spatial Delivery and Chemoresistance Reversal in Tumor Microenvironments

Efficiently overcoming chemoresistance in tumor microenvironments remains a critical hurdle in cancer therapy due to tumor heterogeneity, limited drug penetration, and adaptive resistance mechanisms. Herein, we report the design and application of all-in-one gadolinium-doxorubicin nanoassemblies (GDNAs) for spatially targeted delivery and chemoresistance reversal. These multifunctional nanoassemblies integrate a lanthanide-based component for real-time imaging and doxorubicin for chemotherapy, coupled with bioinformatics-guided small interfering RNAs (siRNAs) to silence key resistance-associated genes such as BCL2 and BIRC5. The GDNAs demonstrate enhanced tumor penetration and specificity for chemoresistant cells, achieving deep tissue delivery and synergistic effects in human-derived organoids and xenograft breast cancer models. Remarkably, GDNAs significantly reduce tumor viability and growth while attenuating invasive potential, showcasing superior therapeutic efficacy compared to conventional treatments. Comprehensive preclinical evaluations confirm their biocompatibility and low systemic toxicity, underscoring the translational potential of this platform. This work introduces a paradigm-shifting strategy by integrating imaging, targeted therapy, and gene silencing to address chemoresistance, offering a versatile approach for personalized cancer treatment.