This study investigates the anti-caries potential of AVHS, a metabolite identified in dental plaque from children and evaluates the therapeutic efficacy of its conjugate form with the antimicrobial peptide RWWRWW (AVHS@RWWRWW). AVHS was found to inhibit the acid production, and growth of Streptococcus mutans, while exhibiting excellent biocompatibility. When conjugated with RWWRWW, AVHS@RWWRWW demonstrated enhanced anti-biofilm activity and effectively suppressed dental caries development in an animal model. Given that both AVHS and AVHS@RWWRWW can show promise as novel therapeutic candidates for caries prevention, this work would be publishable to Journal of Materials Chemistry B. To improve the current version of the manuscript, I add some comments as described below.

1. The conjugation of AVHS with an antimicrobial peptide (RWWRWW) is a promising strategy to enhance its anti-caries effect. However, the current safety evaluation relies primarily on short-term histological observations (H&E staining) and cell co-culturing. Considering potential clinical applications, a more comprehensive assessment of systemic toxicity is necessary. This may include evaluating effects on gut microbiota, immune responses, and chronic exposure.

2. In terms of growth curve of S. mutans (Figure 4B), all the groups entered a stable phase after 14 h; the difference would be only distinct at 6h. I believe that the result is overstated. Moreover, when I look through the acid production curve, AVHS seems to cause the larger acid production than the control at 12h. Further discussions should be included.

3. While the study includes functional comparison with chlorhexidine in a rat model, the broader contextualization of AVHS and AVHS@RWWRWW against other existing therapeutics—such as fluoride, and well-known AMPs like LL-37—is limited. A more systematic comparison of efficacy, safety, and mechanism of action would enhance the clinical and scientific relevance of the findings.

4. While the manuscript presents scientifically interesting results, there appears to be a lack of narrative continuity between the Results and Discussion sections. For instance, the structural analysis shown in Figure 3B is introduced in the Results section without sufficient contextual explanation, which may confuse readers unfamiliar with its relevance. The biological interpretation only becomes clear in the Discussion section, which disrupts the logical flow of the paper. It is therefore recommended to briefly contextualize such figures when they are first presented.

5. While the study presents a comparison between rhodamine-labeled AVHS and the AAAA peptide to demonstrate biofilm-targeting capability (Figure 4D), the use of AAAA alone as a control may be insufficient to establish the sequence specificity or the functional importance of individual residues. In particular, the authors claim that as the presence of histidine residues confers a weak positive charge, they expect the capacity for electrostatic interactions with anionic biofilm components and bacterial membranes. To validate that the observed biofilm targeting is truly sequence-dependent, additional control peptides are necessary. For instance, a histidine-deletion variants (e.g., AVAS) would offer more rigorous comparative evidence.

The authors successfully performed additional experiments to compare the performance of their newly found peptide with the previous ones, demonstrating its better capability. Moreover, most comments that I raised were well addressed. Thus, I recommend the acceptance of the revised manuscript.