Objectives: to evaluate the effect of smear-layer deproteinization using papain gel and SPRG-adhesive on marginal-gap, anti-demineralization of enamel and dentin after chemical pH cycling and assess acid-base resistance zone (ABRZ) characteristics. Methods: Cylindrical cavities were prepared cervically in thirty-two extracted premolars. Teeth were divided into two pretreatment groups (n = 16); deproteinization with papain enzyme gel (Papacarie Duo, Brazil) for 60 s, and no-deproteinization. Each group was subdivided by adhesive type (n = 8); SPRG-based (FL Bond II, Shofu, Japan), and Silica-based (Clearfil SE Bond 2, Kuraray Noritake Dental Inc., Japan). Cavities were restored with flowable composite, followed by a 4-day pH-cycling (6 h demineralization and 18 h remineralization). Specimens were immersed in Rhodamine B, sectioned perpendicularly and evaluated by confocal laser scanning microscopy for wall lesion depth (WLD), outer lesion depth (OLD), complete demineralization, and the marginal-gap length. ABRZ ultrastructure and thickness were assessed using scanning electron microscopy. Results: For enamel, The silica-based adhesive exhibited a significantly higher WLD, OLD and complete demineralization compared to SPRG-based adhesive in both pretreatment conditions (p < 0.05) while insignificant difference in the marginal-gap depth between groups (p > 0.05). For Dentin, complete demineralization and marginal-gap were significantly higher for silica-based adhesive without deproteinization compared to SPRG-based adhesive with deproteinization (p < 0.05). Deproteinization increased ABRZ thickness in both adhesives. Conclusions: SPRG-based adhesive enhances resistance to demineralization during acidic challenge at the mid-/high-micron levels, While enzymatic smear layer deproteinization using papain gel increases the thickness of ABRZ at the micron level. Clinical significance: A simple chairside protocol that combines papain-based smear-layer deproteinization with SPRG-based self-etch adhesive may enhance interfacial demineralization resistance. This synergy could reduce marginal gaps and demineralization at restoration borders, thereby lowering the risk of secondary caries and extending restoration longevity in practice. © 2025 Elsevier Ltd