Size switchable nanomodulator achieving ratio-precise dual-drug codelivery for synergistic glutamine metabolism modulation in pancreatic cancer.

Under the nutrient-deprived tumor microenvironment (TME) and near-universal KRAS mutations, pancreatic ductal adenocarcinoma (PDAC) exhibits voracious addiction to glutamine metabolism. This aberrant metabolism not only sustains the rapid proliferation of malignant cells, but also shapes a tumor-permissive TME characterized by stromal desmoplasia and immunosuppression, culminating in the clinical refractoriness of PDAC. Although multi-target synergistic modulation of glutamine metabolism is recognized as a requisite antitumor strategy, its implementation is still hampered by the uncontrolled in vivo multi-drug biodistribution. Therefore, glutamine metabolism modulation is in urgent need of precision codelivery of multiple drugs. Herein, we propose an upstream-downstream synergistic glutamine metabolism modulation strategy and develop a size switchable metabolic nanomodulators (J&V@T-PPLN NPs) for precision codelivery of metabolic modulators. This nanomodulator achieves in vivo ratio-precise dual-drug codelivery, synergistically blocking the uptake and utilization of glutamine by PDAC cells. Beyond cutting off nutrient supply to malignant cells, the nanomodulator also demonstrates the capacity to remodel the TME and reactivate antitumor immunity, thereby eliciting enhanced tumor suppression. Through the ratio-precise codelivery system, this study discussed the possibility of translating in vitro validated synergistic metabolism modulation into a controllable in vivo combination therapy modality, providing a generalizable strategy for metabolism modulating cancer therapy and the rational design of precision drug delivery systems.