Diabetes mellitus-associated erectile dysfunction (DMED) is characterized by impaired nitric oxide signaling, microvascular injury, neuropathy, metabolic dysfunction, and cavernosal remodeling. These abnormalities may limit responses to phosphodiesterase type 5 inhibitors and compromise regenerative treatment. This focused narrative review examines the potential of nanotherapeutic delivery and microenvironment modulation to address these pathological barriers. We discuss catalytic nanozymes, hypoxia/reactive oxygen species-responsive neurotrophic constructs, mitochondria-targeted piezoelectric systems, fructose-1,6-bisphosphatase 1 (FBP1) mRNA-loaded lipid nanoparticles, and extracellular vesicle–hydrogel composites. By distinguishing cell experiments, interventions in diabetic animals, human observational studies, and early clinical experience with related non-nanoparticle interventions, we compare representative platforms in terms of mechanism, administration route, functional endpoints, biodistribution, duration of effect, and safety. Human functional studies provide strong evidence for impaired nitric oxide signaling, whereas therapeutic strategies targeting lactate metabolism, lactylation, ferroptosis, and mitochondrial turnover remain predominantly at the preclinical stage. We further discuss the potential value of candidate clinical phenotypes and exploratory biomarkers for future patient stratification and examine key translational challenges, including local dosing feasibility, off-target exposure, repeated-dose immunogenicity, reproductive safety, and manufacturing consistency. Overall, current findings provide a mechanistic rationale and research direction for further development of DMED nanotherapies. Further preclinical validation and clinical studies are needed to establish their efficacy, safety, and potential advantages over standard treatment.