Inclusion Criteria:
1. Evidence of a primary (e.g., not secondary to endovascular therapy of proximal vessel occlusion) distal medium vascular occlusion defined as occlusion of the co/non-dominant M2 segment\*, M3, or M4 segment of the middle cerebral artery (MCA), the anterior cerebral artery (ACA) (A1, A2, A3, or A4 segments), or the posterior cerebral artery (PCA) (P1, P2, P3, or P4 segments);
\* Co/non-dominant M2 segment vessel diameter should not exceed 2.0 mm. Co-dominant supplying 50% of the MCA territory vs non-dominant supplying \<50% of the MCA territory.
2. Age ≥18 years;
3. Premorbid mRS 0-1;
4. Evidence of a disabling stroke defined as follows:
1. Baseline National Institutes of Health Stroke Scale (NIHSS) score ≥4 at the time of randomization.
2. NIHSS 2-3 with disabling deficit including significant aphasia, neglect, hemianopsia, or hemiparesis/ loss of hand or leg function as established by the treating team in context of the patient's life.
5. Less than 50% core in the territory supplied by the occluded vessel as evident by hypodensity and loss of grey-white border on NCCT or ADC \<620 mm2/s on diffusion MRI or rCBF\<30% on CTP after 6h of symptom onset.
6. Time from onset (or time last seen well) to treatment within 4.5-24 hours;
7. Informed consent obtained from patient or acceptable patient surrogate.
Exclusion Criteria:
1. Received intravenous thrombolysis prior to randomization;
2. Allergy to Tenecteplase;
3. Seizures, or other neurological/mental illness at stroke onset if it precludes obtaining an accurate baseline NIHSS;
4. Patients planned to undergo MT or other endovascular treatments (e.g., intra-arterial thrombolysis);
5. Systolic blood pressure\>185 mmHg or diastolic blood pressure\>110 mmHg, which cannot be controlled by antihypertensive drug(s);
6. Acute intracerebral hemorrhage identified by CT or MRI;
7. Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT or MRI scan is normal;
8. Subjects with occlusions in multiple vascular territories (e.g., bilateral or multi-territorial anterior circulation, or anterior/posterior circulation);
9. Contraindication to imaging with MR or CT with contrast agents;
10. Known genetic or acquired bleeding diathesis, or received warfarin and INR \> 1.7; or treated with direct oral anticoagulant agents in the prior 48 hours;
11. Platelets \<100×109/L, APTT \> 40 s, or PT \>15 s; Blood glucose \<50 mg/dl (2.7 mmol/L) or \>400 mg/dl (22.2 mmol/L);
12. Severe renal failure, defined as serum creatinine \> 3.0 mg/dl (or 265.2 μmol/l) or glomerular filtration rate (GFR) \< 30, or patients requiring hemodialysis or peritoneal dialysis;
13. Active internal hemorrhage or at high risk of bleeding, e.g., major surgery, sever trauma or gastrointestinal or urinary tract hemorrhage within the last 2 weeks, or arterial puncture at a non-compressible site within the previous 7 days;
14. Ischemic stroke or myocardial infarction in previous 3 months, previous intracranial hemorrhage, severe traumatic brain injury or intracranial or intraspinal operation in previous 3 months, or known intracranial neoplasm, arteriovenous malformation or giant aneurysm;
15. Life expectancy \< 1 year;
16. Patients who cannot adhere to the trial protocol or follow-up;
17. Currently participating in other clinical trials;
18. Pregnant or lactating women;
19. Any other condition that, in the opinion of the investigator, could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study.
