<p>Alpha-therapy for hard-to-treat oncological diseases such as colorectal cancer has drawn significant attention. However, the development of required radiopharmaceuticals for effective delivery and retention of α-radionuclides is very challenging. In the current work, highly efficient radiopharmaceutical form is designed and developed based on polylactide nanoparticles (PLA NPs) labeled with radium-223 (²²³Ra - highly powerful <i>α</i>-emitter) to apply ²²³Ra-labeled PLA NPs in alpha-therapy of colorectal cancer. The developed radiopharmaceuticals exhibit a high radiolabeling yield (e.g. &gt; 90%) and radiochemical stability (&gt; 95%). Depending on the medication administration route (systemic or local injection), the therapeutic effect from ²²³Ra-labeled PLA NPs is non-identical. In particular, tumor volumes in mice are reduced substantially, by approximately ~ 67% for local administration (LA) and ~ 59% for systemic administration (SA) of ²²³Ra-PLA NPs. Additionally, the biodistribution of ²²³Ra-PLA NPs varies depending on the administration route. The direct radiometry analysis does not reveal any significant distribution of radiolabeled PLA NPs within healthy organs and no toxicity towards major organs (e.g. heart, lungs, liver, kidneys, and spleen) was detected. Thus, this work demonstrates the development of radiopharmaceuticals based on ²²³Ra-labeled PLA NPs as universal platform with variable medication administration route for effective alpha-therapy of colorectal cancer.</p>