In an embodiment, a pH-responsive drug delivery composition for prolonged drug delivery to a mucosal surface is provided. At acidic pH, the matrix self-seal and forms entity that protects the peptide/drug inside. Upon contact with fluids at neutral pH, the platform forms swollen gel-like matrix that can protect their cargoes, opens and adheres to mucosal surfaces and release their cargoes over extended period of time (e.g., up to one week). In some embodiments, the composition includes a polymer matrix comprising two or more layers and/or polymers, an agent, and one or more of a protease inhibitor and an absorption enhancer; and an enteric coating or capsule encapsulating the polymeric matrix. Methods of making and using the drug delivery platforms are also provided.