Synthetic polypeptides are of great importance in biomedical applications as they are directly modelled on natural proteins and can mimic their functions in biological systems. Thus, synthetic polypeptides display properties such as biocompatibility, biodegradability, bioavailability, bioadhesion and could find applications in drug delivery, tissue engineering, implants, therapeutics. The availability of wide range of functionality of the synthetic polypeptides arising from the vast pool of natural and non-natural amino acids has been used to modify and to impart new functionalities to the synthetic materials such as organic/inorganic nanoparticles, surfaces, synthetic polymeric architectures, films. This new class of hybrid materials with enhanced biocompatibility are advantageous over their constituent components and show promising candidature in advanced biomedical applications. N-carboxyanhydride Ring Opening Polymerization (NCA-ROP) is a lucrative technique to synthesize polypeptides with controlled molecular weights and narrow polydispersities. Surface intiated N-carboxyanhydride ring opening polymerization (SI-NCA-ROP) by an immobilized intiator has been investigated to teather synthetic polypeptides onto the desired material surfaces. SI-NCA-ROP has been employed from silica nanoparticle surfaces to engineer synthetic polypeptide grafted smart hybrid materials capable of changing microscopic properties according to the changes in pH of the external micro- environment. These silica polypeptide hybrids have shown their applicability in pH responsive cargo release systems. Similarly, surface grafted synthetic polypeptides have been used to modify and improve dispersion properties of iron-oxide magnetic nanoparticles useful in imaging and drug delivery applications. Grafting of highly hydrophilic glycosylated polypeptides have shown improved aqueous dispersion properties of these inorganic nanoparticles useful for MRI imaging and bio-recognition. In an extended study, polypeptides comprising two amino acids have been grafted from iron oxide nanoparticle surfaces to engineer new hybrids with excellent aqueous dispersibility and siRNA vector ability. These co-polypeptide grafted nanoparticle hybrids shown to retain their bio-recognition ability besides improving aqueous dispersibilty and imparting siRNA vectorability, which highlights their applicability as theranostics. In summary, we have presented novel polypeptide hybrid materials by SI-NCA-ROP and their advanced biomedical applications.