<p>Erectile dysfunction compromises men’s quality of life and fertility. Mesenchymal stromal cell injection therapy holds clinical promise, yet its efficacy is limited by poor cell retention and survival in the corpus cavernosum due to rapid blood flow, elevated reactive oxygen species and inflammation. Here, we show that mesenchymal stromal cells surface-engineered with polydopamine nanoparticles conjugated to antibodies against vascular cell adhesion molecule 1 exhibit enhanced retention, survival, and therapeutic efficacy in erectile dysfunction. We demonstrate that the multivalent antibodies guide the cells to inflamed cavernosal endothelium, while polydopamine mitigates reactive oxygen species‑induced damage and improves the inflammatory microenvironment. We show that the underlying engineering process is rapidly achievable under mild conditions, minimizing the impact on cell viability. We find that surface-engineered mesenchymal stromal cells display improved survival under high reactive oxygen species stress and enhanced targeting capabilities in vitro. In rat models of erectile dysfunction, we demonstrate that the engineered cells achieve robust cavernosal retention, reduce local reactive oxygen species and inflammation, reverse tissue pathology, and restore erectile function. We further validate their efficacy in beagle models, confirming cross-species translational potential. Thus, this study provides a facile and translatable surface engineering strategy to overcome key bottlenecks in mesenchymal stromal cell-based erectile dysfunction therapy.</p>