Receptor Targeting Amplifies Curvature-Driven Cooperative Nanoparticle Internalization under Redox Control

Cooperative nanoparticle (NP) internalization offers a powerful route for drug delivery, yet whether its efficiency can be amplified by receptor-targeting of cargo remains a critical open question. Here, we demonstrate that modifying cargo NPs with a receptor-targeting ligand (RPARPAR for neuropilin-1) dramatically amplifies their bystander uptake initiated by TAT-functionalized NPs (T-NPs). The internalization of targeted silver NPs surged from ∼10 to ∼70 units per cell, compared to that of their nonfunctionalized counterparts from ∼2 to ∼20 units. Combining receptor perturbation experiments with coarse-grained molecular dynamics simulations, we reveal that ligand-receptor binding does not constitute an independent pathway but instead synergizes with membrane mechanics. It amplifies cooperative capture by tethering cargo to the cell surface, enhancing its susceptibility to engulfment within curvature-driven, low-free energy zones. Furthermore, we identify extracellular cysteine as a crucial metabolic checkpoint; its continuous availability is required to maintain cellular redox homeostasis, which gates the underlying macropinocytic machinery. Together, our findings establish an integrated, multilevel mechanism where receptor engagement, membrane mechanics, and cellular metabolism converge to drive highly efficient cooperative internalization. This framework provides rational design principles for engineering next-generation cooperative nanodelivery systems and offers fundamental insights into collective endocytic processes.