Spherical hydrogels made from alginate has been explored and used for biomedical application, although restricted mechanical strength and short-term structural cohesion. In this study, controlling mechanical properties and maintaining the long-term structural integrity of spherical hydrogels could be achieved by creating interpenetrating networks of alginate and aqueous-soluble cellulose with divalent and trivalent ions. We found that processing a dual sequential ionic crosslinking scheme to create IPN of alginate and cellulose with divalent and trivalent ions has synergistic effect to increase moduli and structural stability of hydrogels. As a result, the IPN alginate-cellulose beads demonstrate enhanced resistance to harsh chemical environment as compared to alginate beads and suitability for biomedical applications by encapsulating microbial species and therapeutic agents for controlled release.