Hydrogen‐Bonded Organic Framework Enhanced Dopamine Sensing to Uncover Caffeine's Neuroprotection in Parkinson's Disease

ABSTRACT Caffeine is a promising preventive agent for Parkinson's disease (PD), yet deciphering its neuroprotective mechanism has been hampered by the absence of reliable methods to directly correlate caffeine's actions with dynamic dopamine (DA) fluctuations in the living brain. To address this challenge, we developed a novel electrochemical sensor, Ni@PFC‐1/CNT/CFE, fabricated via Ni 2+ ‐embedded hydrogen‐bonded organic frameworks (Ni@PFC‐1) and carbon nanotube (CNT) modified on a carbon fiber electrode (CFE). The hydrophilicity and size‐exclusion gating effect of Ni@PFC‐1 synergistically prevent protein adsorption on the electrode surface. Molecular dynamics simulations further reveal that the pore channels of Ni@PFC‐1 not only exhibit high selectivity for DA but also effectively inhibit the polymerization of DA's oxidized intermediates on the electrode surface. Using this sensor, we systematically investigated caffeine's neuroprotective effects in PD mice. Our results demonstrate that caffeine exerts neuroprotective effects primarily by inhibiting apoptotic signaling through downregulating Casp9 and Casp3, with this protection evident in both long‐term adaptive and acute settings. This work provides direct in vivo evidence that caffeine confers PD neuroprotection by preserving dopaminergic function and suppressing apoptosis. The sensor design and mechanistic insights presented herein offer new avenues for advancing electrochemical biosensor development and PD preventive strategies.