Herein, the exploration of natural plant‐based “spores” for the encapsulation of macromolecules as a drug delivery platform is reported. Benefits of encapsulation with natural “spores” include highly uniform size distribution and materials encapsulation by relatively economical and simple versatile methods. The natural spores possess unique micromeritic properties and an inner cavity for significant macromolecule loading with retention of therapeutic spore constituents. In addition, these natural spores can be used as advanced materials to encapsulate a wide variety of pharmaceutical drugs, chemicals, cosmetics, and food supplements. Here, for the first time a strategy to utilize natural spores as advanced materials is developed to encapsulate macromolecules by three different microencapsulation techniques including passive, compression, and vacuum loading. The natural spore formulations developed by these techniques are extensively characterized with respect to size uniformity, shape, encapsulation efficiency, and localization of macromolecules in the spores. In vitro release profiles of developed spore formulations in simulated gastric and intestinal fluids have also been studied, and alginate coatings to tune the release profile using vacuum‐loaded spores have been explored. These results provide the basis for further exploration into the encapsulation of a wide range of therapeutic molecules in natural plant spores.