Stiffness‐Transformable Nanoplatforms Responsive to the Tumor Microenvironment for Enhanced Tumor Therapeutic Efficacy

Abstract Herein, we report, for the first time, a unique stiffness‐transformable manganese oxide hybridized mesoporous organosilica nanoplatform (MMON) for enhancing tumor therapeutic efficacy. The prepared MMONs had a quasi‐spherical morphology and were completely transformed into soft bowl‐like nanocapsules in the simulated tumor microenvironment through the breakage of Mn−O bonds, which decreased their Young's modulus from 165.7 to 84.5 MPa. Due to their unique stiffness transformation properties, the MMONs had reduced macrophage internalization, improved tumor cell uptake, and enhanced penetration of multicellular spheroids. In addition, in vivo experiments showed that the MMONs displayed a 3.79‐ and 2.90‐fold decrease in non‐specific liver distribution and a 2.87‐ and 1.83‐fold increase in tumor accumulation compared to their soft and stiff counterparts, respectively. Furthermore, chlorin e6 (Ce6) modified MMONs had significantly improved photodynamic therapeutic effect.