• Stratum 1 (Adult GBM)

• Age ≥ 21 years.

• Histopathologically proven newly-diagnosed de novo GBM (WHO Grade IV glioma, secondary GBM not eligible) that is MGMT low level or unmethylated.

• The tumor must have a supratentorial component.

• Patient must have been enrolled on a screening consent and have had sterile collection of tumor material in a manner suitable for RNA extraction, amplification, and loading of lipid particles (LPs).

• Residual post-surgical disease burden ≤ 3 cm as defined by longest perpendicular diameter of tumor on post-operative MRI.

• Patients must have recovered from the effects of surgery, postoperative infection, and other complications.

• A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively and postoperatively. Pre-op MRI must be performed within 28 days prior to study enrollment. Post-op MRI must be completed within 7 days after surgery. Preoperative and postoperative scans must be the same type.

• Performance Score: (KPS) ≥ 60. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• Bone Marrow:

‣ ANC (Absolute neutrophil count) ≥ 1,000µl (unsupported)

⁃ Platelets ≥ 150/µl (unsupported for at least 7 days)

⁃ Hemoglobin \> 8 g/dL

• Renal:

‣ BUN ≤ 25 mg/dl

⁃ Creatinine ≤ 1.7 mg/dl

• Hepatic

‣ Bilirubin ≤ 2.0 mg/dl

⁃ ALT ≤ 5 times institutional upper limits of normal for age

⁃ AST ≤ 5 times institutional upper limits of normal for age

• Willing to take an antiepileptic medication such as levetiracetam for the duration of RNA-LP vaccinations

• Signed informed consent. If the patient's mental status precludes his/her giving informed consent, written informed consent may be given by the legally authorized representative.

• For women of childbearing potential (WOCBP), negative serum/urine pregnancy test at enrollment (test will be repeated within 72 hours prior to starting TMZ in Stratum 1 patients).

• WOCBP must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug. Refer to Appendix F for definition of WOCBP and guidance on acceptable contraceptive methods.

• Males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.

• Participants with post-surgical neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment.

• Stratum 2 (Pediatric HGG)

• Age \> 3 and ≤ 25 years.

• Histologically confirmed WHO Grade III or IV malignant glioma

• Patient must have been enrolled on a screening consent and have had sterile collection of tumor material in a manner suitable for RNA extraction, amplification, and loading of lipid particles (LPs).

• Residual post-surgical disease burden ≤ 3 cm as defined by longest diameter of tumor on post-operative MRI.

• Patients must have recovered from the effects of surgery, postoperative infection, and other complications.

• A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively and postoperatively. Pre-op MRI must be performed within 28 days prior to study enrollment. Post-op MRI must be completed within 7 days after surgery. Preoperative and postoperative scans must be the same type.

• Performance Score: Karnofsky ≥ 60 for participants \> 16 years of age and Lansky ≥ 60 for participants \< 16 years of age assessed within 2 weeks prior to enrollment. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• Bone Marrow:

∙ ANC (Absolute neutrophil count) ≥ 1,000/µl (unsupported)

‣ Platelets ≥ 100/µl (unsupported for at least 7 days)

‣ Hemoglobin \> 8 g/dL (may be supported)

• Renal: Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m2 or acceptable serum creatinine based on age/gender

• Hepatic:

∙ Bilirubin ≤ 3 times upper limit of institutional normal for age.

‣ SGPT (ALT) ≤ 5 times upper limit of institutional normal for age.

‣ SGOT (AST) ≤ 5 times upper limit of institutional normal for age.

• Participants who are receiving systemically-administered steroids must be on a stable or decreasing dose for \>1 week prior to enrollment. The patient steroid dose should be no more than a dexamethasone-equivalent of 2.8 mg/m2/day. Corticosteroid physiologic replacement therapy for management of pituitary/adrenal axis insufficiency and/or topical administration (e.g. inhaled or dermatologic) is allowed.

• Willing to take an antiepileptic medication such as levetiracetam for the duration of RNA-LP vaccinations.

• A legal parent/guardian or patient must be able to understand and be willing to sign a written informed consent and assent document, as appropriate.

• For women of childbearing potential (WOCBP), negative serum/urine pregnancy test at enrollment

• WOCBP must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug. Refer to Appendix F for definition of WOCBP and guidance on acceptable contraceptive methods.

• Males of child-fathering potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.

• Participants with post-surgical neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment.

• Patients must be enrolled on PNOC COMP prior to enrollment on PNOC020 if PNOC COMP is open to accrual at the enrolling institution.