In this communication, we report a new type of amphiphilic carboxymethyl-hexanoyl chitosan (CHC)-poly(acrylic acid) (PAA) hybrid macromolecule, which was successfully prepared through polymerization of acrylic acid (AA) in the presence of amphiphilic CHC. The chemical structure of the hybrid was characterized by FT-IR and 1H NMR, which confirmed a chemical linkage between the amine groups of CHC and hydroxyl groups of AA. This CHC-PAA hybrid exhibited amphiphilic property as the original CHC rendering the self-assembling capability to be tunable in terms of AA concentration. Compared with the existing pristine chitosan-PAA co-polymers, this CHC-PAA hybrid exhibited a relatively high pH-responsive volumetric change by 10-100 times compared with the existing alternatives reported in the literature. The hybrid nanoparticles showed excellent encapsulation efficiency greater than 90% for a hydrophobic anti-cancer substance, (S)-(+)-camptothecin. A pH-responsive drug release behavior was systematically evaluated. Besides, this hybrid also revealed excellent cytocompatibility towards the MCF-7 and BCE cell lines, which, associated with its structural stability, suggests this new type of CHC-PAA hybrid to be a promising biomaterial for oral drug delivery application.