Novel amphiphilic block copolymers having both hydrophobic poly(methyl methacrylate) (PMMA) and hydrophilic poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) blocks have been designed and synthesized for efficient protein detection in photonic-based sensing. Both the cationic PMMA(117)-b-PDMAEMA(16) and the cationic vinyl-sulfone functionalized PMMA(117)-b-P(DMAEMA(17)-VSTEMA(2)) block copolymers, where VSTEMA is 2-(2-(vinylsulfonyl)ethylthio)ethyl methacrylate, were synthesized from a water insoluble hydrophobic PMMA block, which facilitated the formation of stable overlayers on the silica optical fibers surface. The well-defined structure of the co-polymers was confirmed by gel permeation chromatography (GPC). The presence of the cationic PDMAEMA block and the vinyl-sulfone double bonds led to reversible electrostatic binding of negatively charged proteins like bovine serum albumin (BSA) and non-reversible chemical binding by thiol-ene reactions with cysteine in proteins, respectively. The sensing properties of these materials were assessed and confirmed by ATR-FTIR analysis and by the characterization of fabricated sensing heads on silica optical fibers functionalized with suitably deposited overlayers. The sensing assessment revealed the requirements for deposited overlayer characteristics towards proteins' detection sensitivity and selectivity enhancement.