Smart pH-sensing microencapsulation system programmed to actively respond toenvironmentalpH change has long been considered a key technology in pharmaceuticalindustries and foodsciences. Maintenance of both stability of active materials in harshgastrointestinal (GI) tractenvironments and release at target site-specific pH is a major obstacle inoral drug/vaccinedevelopment. In this study, we developed a first-of-its-kind drug deliverysystem withpH-responsive macropores. Opening and closing of these macropores depend on pHto meet thecritical requirements of intestine-targeted drug delivery system, providingstability in stomachand rapid release in intestine. To this end, we developed pored hollowmicroparticles (MPs)made of anionic copolymer using an Oil-in-Water (O/W) emulsion method. Weobserved thatfreeze-drying of MPs induced closure of macropores on their surface, probablydue to thedecrease of glass transition temperature via surfactant incorporation and/orphysicochemicalcharacteristics of polymer-water and polymer-polymer interaction duringdehydration process.The closing and opening behavior of the sealed macropore on MPs in response topH changewere confirmed after being subjected to simulated gastric pH (2-hr incubationat pH 2.0) andintestinal pH (4-hr incubation at pH 7.1), respectively. Time dependentrelease behavior ofingredients through pH-sensing pores was tested using two different types ofmodel drugs(sulforhodamine b and 100 nm sized fluorescent nanoparticles). The intact,closed structure ofthe dye-encapsulated macropore was maintained in simulated gastricenvironment. Subsequentexposure of the same sample to simulated intestine environment induced poreopening, whichcaused release of the ingredients from MPs. To demonstrate the applicabilityof ourmicroencapsulation system for active biomolecules, lactase enzymes wereencapsulated in MPs.Theses MPs displayed more than 15 ti