Remineralization Potential of Self-Assembling Peptides Versus Fluoride Agents in White Spot Lesions: A Systematic Review.

White spot lesions (WSLs) are early manifestations of enamel demineralization, commonly observed in orthodontic patients. Traditional fluoride therapies promote surface-level remineralization but often fall short in addressing subsurface mineral loss. Self-assembling peptides (SAPs), particularly P11-4, have emerged as biomimetic agents capable of penetrating lesions and facilitating deeper enamel regeneration. This systematic review aims to compare the remineralization potential of SAPs and fluoride agents in managing WSLs, evaluating both clinical efficacy and underlying mechanisms. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in PROSPERO (CRD42024622963), an extensive literature search was conducted across PubMed, MEDLINE, Embase, Cochrane, Scopus, and grey literature from January 2000 to December 2024, which yielded 1,028 potential records. After screening 665 titles, 180 abstracts, and 60 retrieved full texts, seven clinical studies, all randomized or controlled clinical trials, met the eligibility criteria. Each study was assessed for risk of bias using the Cochrane RoB 2 tool, and evidence quality was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. A meta-analysis was not performed due to methodological heterogeneity; therefore, results were synthesized narratively. SAP P11-4 demonstrated superior subsurface remineralization compared to fluoride in all included studies, with DIAGNOdent measurements showing reductions ranging from 23% to 41%. Combined SAP-fluoride therapy yielded enhanced outcomes. Although visual changes (International Caries Detection and Assessment System (ICDAS) scores) were often indistinguishable between groups, significant differences in mineral recovery were consistently reported. SAP P11-4 is a promising, minimally invasive alternative to fluoride for managing WSLs, especially in orthodontic patients. Its capacity for deep remineralization highlights its potential as a next-generation caries management tool. However, findings are based on short-term clinical trials, and further long-term randomized studies are recommended to validate and optimize clinical protocols.