Zeolitic imidazolate frameworks (ZIFs) have been widely investigated for separation, gas adsorption, catalysis and biotechnology. Their practical application, however, can be hampered by their structural instability in humid acidic conditions. Here, guided by density functional theory calculations, we demonstrate that the acidic stability of two polymorphic ZIFs (i.e. ZIF-8 and ZIF-L) can be enhanced by incorporating functional groups on polypeptides or DNA. A range of complementary synchrotron investigations into the local chemical structure and bonding environment suggest that the enhanced acidic stability arises from the newly-established coordinative interactions between the Zn centers and the inserted carboxylate (for polypeptides) or phosphate (for DNA) groups, which both have lower pKas than the imidazolate ligand. With functional biomolecular homologues (i.e. enzymes), we demonstrate a symbiotic stability reinforcement effect, i.e. the encapsulated biomolecules stabilize the ZIF matrix while the ZIF exoskeleton protects the enzyme from denaturation.