© 2022 Elsevier LtdMimicking extracellular matrix (ECM) of native tissue by tissue-engineered constructs is critical to induce regeneration of the damaged site. In this study, coaxial electrospinning of core/shell poly(methyl methacrylate) (PMMA)/silk fibroin (SF) fibers was optimized for the first time to provide ECM-like microenvironment for new tissue formation by utilization of a new collector design for obtaining homogeneously deposited mats from the collector screen. SF-shell was produced to increase cell-affinity of fiber surfaces whereas PMMA-core was designed to support the tissue mechanically during regeneration. PMMA/SF membranes were characterized. Morphology of core/shell PMMA/SF fibers resembled neat SF (ribbon-like) fibers rather than neat PMMA (cylindrical) fibers since SF constituted the shell part. The average diameter of PMMA/SF fibers (2.51 μm) lied in between the neat counterparts (PMMA: 2.40 μm and SF: 2.84 μm). The morphological and chemical properties affected the water contact angle and porosity of the mats, leading to the highest hydrophilicity for SF mats and the highest porosity for PMMA mats among the groups. X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) confirmed the core/shell structure of PMMA/SF fibers. The combination of these remarkably different polymers (synthetic, hydrophobic, brittle PMMA and natural, hydrophilic, flexible SF) resulted in intermediate mechanical properties of PMMA/SF mats both in dry and wet conditions by preserving fibrous and porous structures in the core/shell form unlike the neat mats. Thermogravimetric analyses (TGA) showed the highest mass loss for PMMA/SF mats which lost 13.9% of their initial weight unlike the neat counterparts. In vitro hydrolytic & enzymatic degradation studies revealed that PMMA/SF had the weight loss between those observed for SF and PMMA mats in the presence and absence of enzymes while possessing the highest water uptake capacity. SEM examinations of mats after 14 days of hydrolytic degradation demonstrated the SF-shell of the fibers were fused at the intercept points of the PMMA/SF network while the PMMA-core acted as a separating backbone and preserved fibrous, and hence porous architecture of the mats. Cell culture studies demonstrated that human dental pulp stem cells (DPSC) were able to attach and proliferated on PMMA/SF mats while a lower degree of cell spreading on PMMA mats was observed. DPSC adhesion was improved by SF-shell in PMMA/SF group. In conclusion, electrospun composite mats composed of core/shell PMMA/SF fibers could be considered a promising candidate for tissue engineering applications and drug delivery strategies.