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• The way for arterial and venous thrombus are treated should also be varied. • Smaller system favors penetration, while larger one promotes trapping in thrombus. • Physical-matched nano-systems show advances in specific arteriovenous thrombolysis. The differences of physiology, fluid parameters and core structures of thrombus in artery and vein determine the distinct ways for arterial and venous thrombolytic treatments. As an effective drug delivery strategy, physical-matching of nano-delivery system and clot structure will lead to significant advances in specific arteriovenous thrombolysis treatment. We fabricated mesoporous silicon nanoparticles (MSNs) with different sizes (MSN-S: ∼40 nm, MSN-M: ∼70 nm, MSN-L: ∼110 nm) cloaked with platelet membrane (termed PNPs). Results demonstrated that PNP-S (small-sized PNP) exhibited the optimal penetration effect in the both carotid arterial thrombus and deep venous thrombosis (DVT) rat model. However, the enrichment effects in the arterial and venous thrombus were distinct. Upon the action of blood flow shear stress, PNP-S had a better enrichment effect in the carotid arterial thrombus rat model compared with the other groups, while PNP-L (large-sized PNP) showed the best penetration and enrichment efficiency in the DVT rat model. After loading with 100 U/g urokinase (UK) (termed UNPs), large-sized UNPs (UNP-L) and small-sized UNPs (UNP-S) respectively yielded the best thrombolytic effect in the DVT and carotid arterial thrombus rat model, which was near to that of high-dose UK (200 U/g). These results revealed that the physical-matching brought by size adjustment optimized the penetration and retention of nano-delivery system in various thrombi, and eventually enabled specific and effective arteriovenous thrombolysis. [ABSTRACT FROM AUTHOR]