Yincong Zhu, Jianxiang Huang, Yuji Sun, Zhimin He, Weiwei Feng, Huiming Ren, Yongzhao Su, Zhehao Wang, Ying Piao, Youqing Shen, Zhuxian Zhou
Nanoparticle rigidity is a critical yet poorly understood regulator of nano-bio interactions, but decoupling rigidity from other properties (size, charge) remains challenging. Here, we synthesize ultrahigh-generation dye-cored polylysine dendritic dots (PDDs) with precisely tunable rigidity (Young's moduli: 0.93-1.90 GPa), enabling a systematic study of rigidity effects in megadalton dendrimers. These PDDs, produced at the gram scale with close size/charge but generation-dependent stiffness, reveal a striking mechanobiological trade-off: Stiffer PDDs exhibit enhanced cellular uptake, transcytosis, and deep penetration in three-dimensional (3D) tumor spheroids, while softer ones show prolonged blood circulation and superior tumor accumulation. This work deciphers rigidity's dual role in nano-bio interactions, presenting PDDs as a versatile model for mechanobiology studies and providing actionable design principles for next-generation drug delivery systems.