We compared the effectiveness of these EVs in targeting tumour cells in the mice between i.v tail administration and transdermal MN encapsulation and assessed the organ distribution, antitumour efficacy and safety of doxorubicin‐loaded CD38‐EVs (CD38‐EVs‐Dox) using these two methods, aiming to innovate delivery strategies for engineered EVs in targeted therapy of plasmacytoma. Here, CD38 is linked to plasmacytoma.