Local periodontal injection, systemic heart repair: A dual-functional hydrogel for non-invasive concurrent treatment of periodontitis and myocardial infarction

Periodontitis and myocardial infarction (MI), the leading cause of mortality worldwide, represent globally prevalent inflammatory diseases with bidirectional pathophysiological links. Despite the urgent demand for non-invasive strategies capable of alleviating local periodontal destruction while mitigating associated systemic cardiovascular complications, no integrated treatment modality currently exists. To address this challenge, a protein-loaded antibacterial hydrogel, thiolated chitosan/AMP-PEG-maleimide (C1.5P4/BMP-2), with novel sustained protein release properties was developed. This hydrogel features an interconnected microporous architecture that: (1) enables high-efficiency BMP-2 protein encapsulation, (2) preserves protein bioactivity while ensuring sustained release, thereby addressing the recognized challenge of hydrogel-based protein delivery, (3) confers potent antibacterial properties, (4) facilitates remote cardiac function improvement by resolving periodontal inflammation. In murine models, locally, it attenuated alveolar bone loss (2-fold greater bone regeneration vs controls) while systemically improving post-MI cardiac function (75.6% higher ejection fraction). Mechanistically, the hydrogel's protein-protective microenvironment synergized with its antimicrobial action selectively inhibiting Gram-negative (G − ) anaerobic pathogens (primary periodontal culprits) while enriching Gram-positive (G + ) commensals, regulating biofilm G − /G + ratio. Concomitantly, this dual action modulates the oral-cardiac inflammatory axis, specifically downregulating B2 cell/TNF-α signaling to mitigate systemic inflammation associated with MI. Collectively, this study presents a novel non-invasive protein-stabilizing hydrogel that addresses periodontitis-MI comorbidity through sustained osteogenic factor delivery coupled with microbiome-immune modulation. • The first dual-targeting hydrogel for periodontitis-MI comorbidity via a single periodontal injection. • High protein loading capacity with sustained bioactivity and tunable injectability for periodontal pockets. • Gram-negative selective antimicrobial and osteogenic synergy of the hydrogel for periodontitis. • Dual-organ healing ability of the hydrogel via mediating microbiome-immune crosstalk.