Hydrogen-bonded multilayers of a neutral polymer (poly(N-vinylpyrrolidone), PVPON) with poly-(methacrylic acid) (PMAA) were used as templates to introduce cross-links between PMAA layers using carbodiimide chemistry and ethylenediamine as a cross-linking agent. Upon exposure to high pH, PVPON is completely released from the hydrogel matrix, producing surface-attached PMAA hydrogels. When such hydrogels are deposited at the surface of silica particles, and the particle core is subsequently dissolved, hollow one-component hydrogel capsules are produced. PMAA hydrogel films and hollow capsules underwent reversible, large (factors of 2 or 3) changes in size in response to changes in solution pH and/or ionic strength. The capsules were used for entrapment and storage of macromolecules such as 500 kDa FITC-dextran by "locking" the capsule wall with an electrostatically associating polycation, poly-N-ethyl-4- vinylpyridinium bromide (QPVP). The release of the encapsulated macromolecules was achieved under high salt concentrations (0.6 M NaCl) when QPVP dissociated from the capsule wall. The pH and salt response of these PMAA hydrogel capsules and the polycation-controlled encapsulation of macromolecules hold promise for applications in biomedicine and biotechnology. © 2006 American Chemical Society.