Autonomous Braking of Host‐Guest Nanoparticles for Enhanced Tumor Tissue Penetration and Retention

Abstract The tumor microenvironment (TME), characterized by high interstitial pressure, acidic pH, and dense extracellular matrix, poses significant barriers to efficient drug delivery, limiting the therapeutic efficacy of conventional nanomedicines. Although self‐propelled nanoparticles have emerged as promising tools for enhancing intratumoral penetration, their excessive propulsion often compromises drug accumulation at the target site due to the absence of controllable braking mechanisms. Herein, the design of an acid‐responsive Janus catalytically active nanoparticle is reported and denoted as SiO ₂ @PDA‐Pt‐Lox (SPPL), which is capable of active braking in response to TME conditions. The nanoparticle is powered by the enzymatic generation of O ₂ , catalyzed by lactate oxidase (Lox) and platinum (Pt), enabling autonomous motion within tumors. Upon exposure to the acidic TME, the PDA layer undergoes acid‐induced depolymerization at pH 5.0, which in turn induces the detachment of the Pt‐Lox propulsion unit, thereby achieving in situ deceleration and braking. This transition from active motion to passive retention enhances the accumulation of Doxorubicin‐loaded nanoparticles at the tumor site, improving chemotherapeutic efficacy. This study provides a proof‐of‐concept for developing environment‐adaptive catalytically active nanoparticles capable of self‐regulated braking, offering a promising strategy for overcoming the barriers of solid tumors and advancing the clinical translation of nanoparticle‐based drug delivery systems.