Bioactive membranes with growth factors that mimic the physiological microenvironment of periodontal tissues have shown great potential for guided tissue regeneration (GTR). However, the loss of bioactivity and the uncontrolled drug release in conventional membranes limit their efficacy. In addition, membranes with local infection control ability would provide additional benefits to regeneration. In this work, nanoengineered membranes with growth factor and antibiotic delivery capabilities were developed to achieve dual functions for efficient GTR. Mesoporous silica nanoparticles (MSNs) with large pores with the ability to encapsulate and preserve the bioactivity of growth factors were used as the core, and antibiotics were loaded in shell nanofibers with coaxial electrospinning. A sustained release behavior of the growth factor was observed, and the nanoparticle-encapsulated core–shell nanofibers show better ontogenetic regeneration abilities toward bone marrow stromal cells, compared to current commercial Bio-Gide membranes. In addition, the drug-loaded nanocomposite core–shell nanofibers showed excellent antibacterial properties toward Gram-positive, Gram-negative, and multispecies oral bacteria. The MSNs-embedded core–shell nanofiber system provides an attractive strategy to deliver dual drugs for GTR with better performance