Semi-synthetic biopolymer complex (SSBC) nanoparticles were investigated as a potential oral drug delivery system to enhance the bioavailability of a poorly water-soluble model drug acyclovir (ACV). The SSBCs were prepared from cross-linking of hydroxyl groups on hyaluronic acid (HA) with poly(acrylic acid) (PAA) resulting in ether linkages. Thereafter, conjugation of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) onto HA-PAA was accomplished using a 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS)-promoted coupling reaction. Nanoparticle powders were prepared by spray drying of drug-loaded SSBC emulsions in a laboratory nano spray dryer. The prepared SSBC was characterized by Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), 1H nuclear magnetic resonance (NMR) imaging, and X-ray diffraction (XRD) spectroscopy. The average particle size was found to be 257.92 nm. An entrapment efficiency of 85% was achieved as ACV has enhanced affinity for the hydrophobic inner core of the complex. It was shown that SSBC improved the solubility of ACV by 30% and the ex vivo permeation by 10% compared to the conventional ACV formulation, consequentially enhancing its bioavailability. Overall, this study resulted in the successful preparation of a hybrid chemically conjugated SSBC which has great potential for enhanced oral absorption of ACV with possible tuneable ACV permeability and solubility, producing an “intelligent” nanoenabled drug delivery system.