Methods and compositions for delivering macromolecules to or via the respiratory tract, such that the macromolecules exhibit improved local and/or systemic bioavailability are provided. Such methods utilize lipid-based microstructures formed in combination with at least one bioactive macromolecule, which have a superior ability to rapidly release the bioactive macromolecule(s) thereby resulting in improved local and/or systemic bioavailability of the bioactive macromolecule(s). Such improved bioavailability is believed to be due, in part, to reduction of scavenging by bronchoalveolar macrophages and/or mucociliary clearance. Compositions with improved bioavailability are provided comprising a plurality of lipid-based microstructures formed in combination with at least one bioactive macromolecule, wherein the bioavailability of the bioactive macromolecule is improved by modifying the rate of release of the bioactive macromolecule from the microstructure thereby reducing scavenging by bronchoalveolar macrophages and/or mucociliary clearance.