The efficacy of current opioid overdose interventions is fundamentally limited by their reliance on bystander detection and administration, leaving unwitnessed overdoses, a predominant cause of fatalities, unaddressed. Herein, we developed an innovative fentanyl-responsive microneedle (MN) patch (iNal patch) engineered as an autonomous harm reduction tool to dynamically release naloxone on demand in response to fentanyl levels. Specifically, the iNal patch integrates mesoporous silica nanoparticles (MSNs) loaded with naloxone. The nanoparticle surfaces are modified by fentanyl-sensitive aptamers, allowing precise and dose-dependent drug release triggered by fentanyl exposure. The engineered MN matrix composed of swellable maleated poly(vinyl alcohol) facilitates rapid skin penetration and interstitial fluid access, ensuring immediate and sustained naloxone release. From in vitro and in vivo studies, the iNal patch was demonstrated to effectively reverse fentanyl-induced opioid overdose symptoms, rapidly restore normal physiological behaviors in mice, and enable multiple responsive drug-release cycles to prevent renarcotization. This proof-of-concept MN platform establishes a new paradigm for materials-based harm reduction, offering an autonomous safety net for high-risk populations independent of human supervision.