Engineering stimuli-responsive extracellular vesicles for enhanced anticancer therapeutics.

Extracellular vesicles (EVs), so called nano-sized vesicles shedding out from cells, have emerged as promising nanocarriers for cancer therapy given their high biocompatibility and low immunogenicity. However, their clinical utility remains limited by challenges such as off-target, premature drug release, and rapid clearance. In solid tumors, these issues are further compounded by the hostile biomechanical environment, including stiff extracellular matrix (ECM), elevated interstitial fluid pressure (IFP), and abnormal vasculatures, further complicates drug delivery and therapeutic efficacy. To overcome these limitations, recent efforts have focused on engineering stimuli-responsive EVs that respond to internal stimuli (e.g., pH, enzymatic activity, redox imbalance) or external stimuli (e.g., magnetic fields, light, ultrasound, temperature), as well as combinations thereof. These smart nanoplatforms have demonstrated a superior capacity in achieving controlled drug release, enhancing tumor targeting, and improving deep tissue penetration. In this minireview, we highlight how stimuli-responsive EVs surpass tumor biomechanics for cancer therapy and discuss key considerations for future development and clinical translation.