Upon intravascular applications, i.e., cancer treatment, nanoparticles (NPs) are required to deliver through blood circulation, sustain serum protein interactions, before they penetrate the blood vessels and reach targeted sites for payload drug release. For a delivery process as such, it is elusive and difficult to comprehend the morphological change of NP surface and evaluate associated effects on its targeted delivery. Herein, we used silica NPs with different surface modifications to demonstrate the morphological impact of NPs during the application of the NP-blood protein interaction, vascular endothelial cell penetration, subsequent targeted delivery and photodynamic therapy efficacy and the morphology were designed for pursuing high drug loading capacity. Compared to solid and mesoporous NPs, we found the spiky tubular NPs facilitated to reserve the NPs' antifouling properties (or shedding of “protein corona”), promoted better endothelial penetration and less destruction in vitro and in vivo. This could be attributed to that those multiple spikes on spiky tubular NPs limited the NP-protein interaction area and promoted the NP-protein steric hindrance. Further in molecular simulations, we determined that the spiky tubular morphological modification on NPs enhanced the interaction free energy, while it lowered the amino acids number and the subsequent frequency in contacting with VE-cadherin of endothelia. As a result, these NPs have advantages in mitigating damages to VE-cadherin stability and endothelial cell integrity. Our finding here suggests that we could exploit the surface morphological modification to design spiky tubular NPs, to improve the NP delivery efficiency while prohibiting the leakiness of vascular endothelial microenvironment, particularly relevant for tumor migration during nanomedicine applications in cancer therapy.