All of Us Pennsylvania (AOU PA) embraces research equity as a fundamental principal and prioritizes engagement and enrollment of diverse participants by bringing the All of Us Research Program to underrepresented and disadvantaged neighborhoods and populations throughout the Commonwealth. As the first site to launch and enroll participants, the AOU PA Program brings 7 years of experience, deep community partnerships, data-driven operations, robust infrastructure, lessons learned, and dedicated staffing to accelerate progress on achieving the enrollment of one million diverse participants across the United States. We have engaged communities and enrolled participants in 38 of the 67 counties in PA. As of October 10, 2023, we enrolled 41,558 Core participants (8.5% of the national cohort), 72% of whom are from underrepresented backgrounds in research. New for AOU PA 2.0 will be the addition of community-based ambassadors - our AOU PA Navigators - and partner organizations - our Community Research Hubs. Navigators and Hubs will represent their communities on our Community Advisory Board, help develop messaging, promote and host engagement and enrollment activities, and directly communicate through personal connections with their friends and neighbors the value of All of Us. Our long-term objective for AOU PA 2.0 is to maintain our successful operations and to establish multiple AOU PA Navigators and Community Research Hubs who can operate independently in their communities with the support of the AOU PA Platform. They will focus on engaging and retaining participants with disabilities and participants who are from primarily Black and Hispanic-Latino communities across PA, with new initiatives in the Philadelphia and Harrisburg regions. At the same time, we will maintain current AOU PA enrollment activities in western and central PA, including those in rural communities. Specifically, we will: Aim 1. Conduct outreach and engagement activities designed in equitable partnership with members of the communities of interest in which engagement and enrollment will occur; and Aim 2. Engage, enroll, and retain participants from populations who are historically underrepresented in biomedical research. We will learn from members of diverse communities how All of Us can best establish and communicate its trustworthiness and research reciprocity using human-centered design, which emphasizes human perspective and empathy at every stage of a design process. We bring community members together in Engagement Studios that provide a safe space, respectful environment, and inclusive approach for co-creating messages and engagement strategies. We will expand our current Engagement Team to include members from marginalized groups who share lived experiences with the communities with whom we partner and the Engagement Team at the Human Engineering Research Laboratories (HERL), which works to ensure that individuals with disabilities from diverse backgrounds can participate in and contribute to assistive technology research. Other partnerships include the Pittsburgh Theological Seminary, several Black churches throughout the state, Casa San Jose, and independent community pharmacies. Our approach will ramp up AOU PA activities in new strategically selected racially and ethnically diverse locations throughout Pennsylvania through personal engagement while expanding our current Enrollment activities in western PA. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions for the opioid crisis and overdose epidemic, including opioid use disorder and stimulant use disorder. The NIH HEAL Initiative bolsters research across NIH to address the national opioid public health crisis and improve treatment for opioid misuse and addiction.