The ANGEL-MeVO-TNK is a multicentered, prospective, randomized, open label, blinded endpoint (PROBE) phase III trial. A total of 488 AIS patients (age ≥18 years) with acute MeVO-AIS (occlusion of the M2/M3, the A1/A2/A3, the P1/P2/P3, and with baseline NIHSS score >5 or disabling stroke with NIHSS score 3-5 [such as neurological deficits in motor strength, language, vision, etc]), will be enrolled. Patients fulfilling all the inclusion criteria and none of the exclusion criteria will be randomized 1:1 into the IA TNK group or the control group after offering informed content.

• The IA TNK group：1) If the patient has not received IVT, IA TNK will be administered as a slow, continuous infusion for super-selective contact thrombolysis in a stepwise manner: an initial dose of 0.0625 mg/kg with a duration of 15 minutes. A repeat angiographic assessment will then be performed; if recanalization is not achieved, an additional dose of 0.0625 mg/kg will be administered over a further 15 minutes (maximum dose 12.5 mg) .

  2) If the patient has received IVT, intra-arterial TNK will be administered as a slow infusion for super-selective contact thrombolysis at a dose of 0.0625 mg/kg (maximum dose 6.25 mg) with a duration of 15 minutes.

• The control group will be given standard medical management.

The study consists of four visits including the day of randomization, 48±12 hours after randomization, and 90±7 days after randomization. Demographic information, symptoms and signs, laboratory test, neuro-imaging assessment neurological function rating scale will be recorded during the program.

The primary outcome is the modified Rankin Scale (mRS) score of 0 to 1 at 90±7 days after onset. The primary safety outcome is the incidence of sICH within 48±12 hours after randomization (ECASS III).

Inclusion Criteria:

Clinical Inclusion Criteria:

1. Age ≥18 years;
2. Pre-stroke mRS 0-1;
3. Within 24 h from symptom onset;
4. Baseline National Institutes of Health Stroke Scale (NIHSS) score >5 or baseline NIHSS 3-5 with disabling deficit (e.g., loss of hand function, aphasia, hemianopia);
5. Informed consent obtained from patients or their legal representatives.

Imaging Inclusion Criteria:

1. Baseline CTA/MRA/DSA diagnosed isolated MeVO, referring to the M2/M3 segment of the MCA, the A1/A2/A3 segment of the ACA, the P1/P2/P3 segment of the PCA;
2. NCCT or MRI DWI imaging showing that the territory of the ischemic infarct volume is less than 50% of the estimated territory supplied by the occluded artery.

Exclusion Criteria:

1. Acute intracranial hemorrhage;
2. ASPECT ≤5;
3. MeVO secondary to spontaneous fragmentation and distal migration of thrombus from an acute large vessel occlusion, or occurring after intravenous thrombolysis (IVT), intra-arterial thrombolysis, or endovascular thrombectomy;
4. Contraindication to TNK;
5. Known severe allergy to contrast agents (excluding mild rash-type allergic reactions);
6. Use of heparin or novel oral anticoagulants within the previous 48 hours with an INR ≥ 1.7;
7. A history of major bleeding within the past 6 months or the presence of conditions such as active gastrointestinal ulcer, aortic dissection, platelet count < 100 × 10⁹/L, etc.;
8. Radiologically confirmed vascular malformations, arterial dissection, intracranial aneurysm (diameter≥3 mm), tumors (except small meningiomas), cerebral vasculitis, cerebral amyloid angiopathy, or other major non-ischemic intracranial diseases (e.g., multiple sclerosis);
9. Acute renal failure, current dialysis, or estimated glomerular filtration rate (eGFR)<30ml/min/1.72m2, and/or serum creatinine>220mmol/L (2.5mg/dl);
10. History of severe liver disease, or aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) and/or glutamyl transferase (GGT) ≥3×upper limit of normal value (ULN) and/or total bilirubin (TBIL) ≥2×ULN;
11. Severe non-cardiovascular comorbidity with an expected life expectancy of less than 3 months (e.g., malignant tumors);
12. Known pregnancy or breastfeeding, or a positive pregnancy test prior to randomization;
13. Current participation in another drug or device clinical trial;
14. Any other condition deemed by the investigator to make the patient unsuitable for participation in the study or to pose a significant risk to the patient (e.g., inability to understand and/or comply with study procedures and/or follow-up due to psychiatric illness, cognitive impairment, or emotional disorders).

The principal researcher holds complete intellectual property rights. The entire research process and data analysis process strictly protected the information of the subjects. There is not a plan to make individual patient data (IPD) available. Sharing IPD will require IRB approval from Tiantan Hospital and other participating institutes in China.

Since the experimental group needs to perform arterial thrombolysis and related operations on patients, the doctors and nurses involved in the study will not be blinded for random patient allocation. However, the grouping of patients will blind neurologists and nurses responsible for conducting neurological, imaging and functional evaluations at baseline and follow-up, as well as collecting clinical outcome data. The randomization information of the patients will also blind the members of the outcome assessment committee.