• • HOF-101 and HOF-102 achieved drug loading capacities of 27% and 29.8%, respectively, enabling reduced therapeutic dosages and minimized adverse effects—critical for clinical translation where off-target toxicity remains a primary failure mode.
• • HOF-TATB exhibited an ultrasound activation threshold of 0.51 MPa with only 5.5% premature drug release, demonstrating superior temporal resolution and safety margins for deep-tissue neuromodulation where unintended activation can cause severe neurological side effects.
• • Release kinetics correlated directly with peak ultrasound pressure and material Ecohesive values, providing a quantitative design rule for tuning mechanoresponsive HOFs—this replaces empirical trial-and-error with predictive engineering, accelerating development cycles.
• • The platform successfully encapsulated deschloroclozapine, dopamine, and procaine, proving versatility across chemically diverse payloads; this broadens applicability from psychiatric neuromodulation to neurotransmitter replacement and local anesthesia, addressing multiple unmet clinical needs.