The emergence of autonomous vehicles (AVs) marks a transformative leap in transportation technology. Central to the success of AVs is ensuring user safety, but this endeavor is accompanied by the challenge of establishing trust and acceptance of this novel technology. The traditional “one size fits all” approach to AVs may limit their broader societal, economic, and cultural impact. Here, we introduce the Persona-PhysioSync AV (PPS-AV). It adopts a comprehensive approach by combining personality traits with physiological and emotional indicators to personalize the AV experience to enhance trust and comfort. A significant aspect of the PPS-AV framework is its real-time monitoring of passenger engagement and comfort levels within AVs. It considers a passenger’s personality traits and their interaction with physiological and emotional responses. The framework can alert passengers when their engagement drops to critical levels or when they exhibit low situational awareness, ensuring they regain attentiveness promptly, especially during Take-Over Request (TOR) events. This approach fosters a heightened sense of Human–Vehicle Interaction (HVI), thereby building trust in AV technology. While the PPS-AV framework currently provides a foundational level of state diagnosis, future developments are expected to include interaction protocols that utilize interfaces like haptic alerts, visual cues, and auditory signals. In summary, the PPS-AV framework is a pivotal tool for the future of autonomous transportation. By prioritizing safety, comfort, and trust, it aims to make AVs not just a mode of transport but a personalized and trusted experience for passengers, accelerating the adoption and societal integration of autonomous vehicles.