Transformable “Bullet Train”-like Nanomotors for Sequentially Overcoming Tumor Delivery Barriers

Chemotherapeutics encounter poor efficacy and serious adverse effects due to multiple delivery barriers. Inspired by the multipower-unit design and adjustable length of bullet train, we designed a "bullet train"-like transformable nanomotor (f-JSN-u)_<i>n</i> to sequentially overcome multiple tumor delivery barriers. Upon administration, these rod-shaped (f-JSN-u)_<i>n</i> assemblies achieved long circulation, and the "bullet train"-like motion enhanced their diffusion across tumor vasculatures and selective tumor accumulation. When reaching tumor sites, local NIR irradiation triggered the disassociation of rod-shaped "bullet train" into individual "carriage" with spherical shape and smaller size, enabling deep tumor penetration and enhanced cellular uptake. In the tumor microenvironment, the self-propelled motion further facilitated deeper tumor penetration, where folate-mediated cellular endocytosis and glutathione-triggered drug release ultimately boosted antitumor efficacy. Our study revealed (f-JSN-u)₃ exhibited a 3.4-fold longer plasma half-life and a >3-fold higher distribution in tumor tissues compared to f-JSN-u, accompanied by significantly enhanced tumor penetration and remarkable antitumor efficacy.