Inclusion Criteria:
* 12-50 years of age (inclusive) at the time of screening
* Diagnosed with sickle cell disease (SCD) with a βS/βS, βS/β0 or βS/β+ genotype.
* Experienced at least 4 severe vaso-occlusive events (VOEs) in the two years before informed consent, despite supportive care measures (e.g., a pain management plan).
* Have a Karnofsky Performance Status (KPS) score (for subjects ≥16 years) or Lansky Performance Status (LPS) score (for subjects \<16 years) of ≥60.
* Have experienced either hydroxyurea (HU) failure at any time in the past or demonstrated intolerance to HU.
* Subject must have been treated and followed for at least two years before informed consent at the medical center that maintained detailed records of their sickle cell disease history.
* Be willing and able to comply with all study procedures and visit schedules.
* The subject and/or their legally authorized representative must voluntarily agree to participate, sign the informed consent form, and be capable of completing all follow-up assessments required by the protocol.
Exclusion Criteria:
* Have any severe active infection (fungal, bacterial, viral, tuberculosis, or other), including active Hepatitis B (defined as serum HBV-DNA ≥2000 IU/mL), active Hepatitis C virus (HCV) infection, positive human immunodeficiency virus (HIV) antibody, or active syphilis.
* Inadequate bone marrow function, as defined by an absolute neutrophil count of \<1.0 x 10\^9/L (\<0.5 x 10\^9/L for subjects on hydroxyurea treatment) or a platelet count \<100 x 10\^9/L.
* Have severe cerebrovascular disease, including a history of significant ischemic or hemorrhagic stroke, abnormal Transcranial Doppler (TCD) flow velocities requiring chronic transfusion therapy (\>200 cm/s), occlusion or stenosis of the circle of Willis, or any history of moyamoya disease.
* Baseline oxygen saturation \< 90% without supplemental oxygen (excluding periods of SCD crisis, severe anemia or infection).
* Baseline carbon monoxide diffusing capacity (DLCO) \< 50% (corrected for Hb) in the absence of infection. If DLCO cannot be assessed due to age or cognitive limitations, there must be a normal respiratory exam, a chest radiograph without pulmonary infiltrates, and oxygen saturation by pulse oximetry ≥ 90% on room air.
* Baseline left ventricular ejection fraction (LVEF) \< 45%
* Clinically significant pulmonary hypertension at baseline, as defined by the requirement for ongoing pharmacologic treatment or the consistent or intermittent use of supplemental oxygen.
* Baseline estimated glomerular filtration rate (eGFR) \<70 mL/min/1.73 m\^2
* Advanced liver disease
* Have a definite contraindication to stem cell collection.
* Have any prior or current malignancy, myeloproliferative disorder, or immunodeficiency disease.
* Have white blood count \<3.0 x 10\^9/L and/or platelet count \<100.0 x 10\^9/L not due to hypersplenism.
* Have a diagnosis of compound alpha-thalassemia (excluding silent carrier).
* Have significant iron overload at screening, defined as severe iron overload on liver MRI, or serum ferritin levels \>2000 ng/mL, or cardiac T2\* \<10 ms.
* Have positive irregular red cell antibodies or platelet antibodies.
* Be eligible for allogeneic hematopoietic stem cell transplantation and have an identified willing, fully HLA-matched donor.
* Prior receipt of gene therapy or allogeneic hematopoietic stem cell transplantation.
* Immediate family member with a known or suspected Familial Cancer Syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome, and familial adenomatous polyposis).
* Have a diagnosed major psychiatric disorder or predisposition that, in the Investigator's opinion, would severely compromise the ability to participate in the clinical study.
* Have an uncorrectable coagulation disorder or a history of severe hemorrhagic disease.
* Have any other condition that, in the opinion of the treating physician, renders the subject unsuitable for hematopoietic stem cell transplantation.
* Have a known allergy to the investigational drug(s) (e.g., plerixafor, busulfan) or their components.
* Have participated in or are currently participating in another interventional clinical study within 3 months before screening.
* Received a live vaccine within 6 weeks before screening.
* Be pregnant or breastfeeding.
* The subject or their partner is unwilling to use medically acceptable effective contraception during the 32-month study period.
* Unable to receive red blood cell transfusion.
* The subject or their parent/guardian is unable to adhere to the study protocol.
* Have any other condition deemed by the Investigator to make the subject unsuitable for participation in this study.
