A protein nanocage formulation with enhanced mucus penetration capability and colloidal stability provides controlled delivery of therapeutic, prophylactic, or diagnostic agents to tumors. A dense coating of a surface altering agent such as polyethylene glycol on self-assembled protein nanocages enhances the rapid and uniform distribution of the formulation at mucosal tissues following topical administration, enhances circulation time following intravenous administration, and enhances penetration into hypoxic tumor cores. The density and the molecular weight of surface altering agents are selected to allow the protein nanocages to also bind to tumor cell receptors and release chemotherapeutic agents after tumor cell uptake. Agents delivered in the formulation have better efficacy compared to carrier-free agents. A method of making the protein nanocage formulation with enhanced mucus penetration and colloidal stability is also provided.