# The Potential of Chronotherapy and Nanotherapy-Based Strategies for Glioblastoma Treatment

**Authors:** Ana Raquel Neves, Rafael Mineiro, Telma Quintela, Diana Costa

PMC · DOI: 10.3390/pharmaceutics18020235 · 2026-02-12

## TL;DR

This paper explores combining chronotherapy and nanotechnology to improve glioblastoma treatment outcomes and reduce side effects.

## Contribution

The paper introduces a novel integrative approach combining chronobiology and nanotechnology for glioblastoma treatment.

## Key findings

- Aligning treatment with circadian rhythms may improve therapy effectiveness.
- Nanoparticles can enhance drug delivery and reduce toxicity.
- Combining chronotherapy and nanotechnology could lead to personalized cancer treatments.

## Abstract

Glioblastoma is the most common and aggressive brain tumour in adults, and despite ongoing efforts, effective treatment remains limited. Standard therapies often face challenges because of the tumour’s specific biology, its aggressive nature, and the presence of certain physiological barriers in the brain that impede chemotherapeutics from reaching their target. Emerging research in circadian biology highlights the role of the internal circadian clock in tumour progression and treatment response. Evidence suggests that aligning therapy to patients’ chronotypes could potentially improve treatment outcomes. At the same time, advances in nanotechnology—including functionalized nanoparticles for drug and/or gene delivery—show promising results while reducing side effects. Additionally, evolving and prominent artificial intelligence tools may significantly contribute to progress in the design of next-generation personalised therapies. This review provides a unique and integrative perspective by examining the hurdles in treating GB and exploring innovative strategies, such as the integration of nanotechnology into chronotherapy protocols, to enhance therapeutic efficacy. The Chronobiology–Nanotechnology combination could not only improve GB patients’ survival rates but also lead to a more effective and less toxic personalised approach, distinguishing this work from previous reviews.

## Linked entities

- **Diseases:** Glioblastoma (MONDO:0018177)

## Full-text entities

- **Genes:** Plk1 (polo like kinase 1) [NCBI Gene 18817] {aka Plk, STPK13}, Yap1 (yes-associated protein 1) [NCBI Gene 22601] {aka Yap, Yap65, Yki, Yorkie}, Rora (RAR-related orphan receptor alpha) [NCBI Gene 19883] {aka 9530021D13Rik, Nr1f1, ROR1, ROR2, ROR3, nmf267}, OPN4 (opsin 4) [NCBI Gene 94233] {aka MOP}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, SLC2A1 (solute carrier family 2 member 1) [NCBI Gene 6513] {aka CSE, DYT17, DYT18, DYT9, EIG12, GLUT}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Erbb3 (erb-b2 receptor tyrosine kinase 3) [NCBI Gene 13867] {aka Erbb-3, Erbb3r, Her3}, RORA (RAR related orphan receptor A) [NCBI Gene 6095] {aka IDDECA, NR1F1, ROR1, ROR2, ROR3, RORa1}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, IDH1 (isocitrate dehydrogenase (NADP(+)) 1) [NCBI Gene 3417] {aka HEL-216, HEL-S-26, IDCD, IDH, IDP, IDPC}, Rela (Rela proto-oncogene, NFKB subunit) [NCBI Gene 19697] {aka p65, p65 NF-kappa B, p65 NFkB}, PDGFRA (platelet derived growth factor receptor alpha) [NCBI Gene 5156] {aka CD140A, PDGFR-2, PDGFR2}, Pdgfrb (platelet derived growth factor receptor, beta polypeptide) [NCBI Gene 18596] {aka CD140b, PDGFR-1, Pdgfr}, per2 (period circadian clock 2) [NCBI Gene 140633] {aka fj43b09, wu:fj43b09}, IDH2 (isocitrate dehydrogenase (NADP(+)) 2) [NCBI Gene 3418] {aka D2HGA2, ICD-M, IDH, IDH-2, IDHM, IDP}, CRY1 (cryptochrome circadian regulator 1) [NCBI Gene 1407] {aka DSPD, PHLL1}, CRY2 (cryptochrome circadian regulator 2) [NCBI Gene 1408] {aka HCRY2, PHLL2}, Bmal1 (basic helix-loop-helix ARNT like 1) [NCBI Gene 11865] {aka Arnt3, Arntl, BMAL1b, MOP3, bHLHe5, bmal1b'}, TIMELESS (timeless circadian regulator) [NCBI Gene 8914] {aka FASPS4, TIM, TIM1, hTIM}, NGFR (nerve growth factor receptor) [NCBI Gene 4804] {aka CD271, Gp80-LNGFR, TNFRSF16, p75(NTR), p75NTR}, ABCB1 (ATP binding cassette subfamily B member 1) [NCBI Gene 5243] {aka ABC20, CD243, CLCS, ENPAT, GP170, MDR1}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, MIR18A (microRNA 18a) [NCBI Gene 406953] {aka C13orf25, MIR18, MIRH1, MIRHG1, MIRN18, MIRN18A}, Mdk (midkine) [NCBI Gene 17242] {aka MK, Mek}, Clock (clock circadian regulator) [NCBI Gene 12753] {aka 5330400M04Rik, KAT13D}, TF (transferrin) [NCBI Gene 7018] {aka HEL-S-71p, PRO1557, PRO2086, TFQTL1}, Cry1 (cryptochrome circadian regulator 1) [NCBI Gene 12952] {aka Phll1}, Per1 (period circadian clock 1) [NCBI Gene 18626] {aka Hftm, Per, m-rigui, mPer1}, SELPLG (selectin P ligand) [NCBI Gene 6404] {aka CD162, CLA, PSGL-1, PSGL1}, TFRC (transferrin receptor) [NCBI Gene 7037] {aka CD71, IMD46, T9, TFR, TFR1, TR}, LINC-ROR (long intergenic non-protein coding RNA, regulator of reprogramming) [NCBI Gene 100885779] {aka ROR, lincRNA-RoR, lincRNA-ST8SIA3}, BMAL1 (basic helix-loop-helix ARNT like 1) [NCBI Gene 406] {aka ARNTL, ARNTL1, BMAL1c, JAP3, MOP3, PASD3}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, NR1D1 (nuclear receptor subfamily 1 group D member 1) [NCBI Gene 9572] {aka EAR1, REVERBA, REVERBalpha, THRA1, THRAL, ear-1}, NFIL3 (nuclear factor, interleukin 3 regulated) [NCBI Gene 4783] {aka E4BP4, IL3BP1, NF-IL3A, NFIL3A}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, Nr1d2 (nuclear receptor subfamily 1, group D, member 2) [NCBI Gene 353187] {aka RVR, Rev-erb}, LGMN (legumain) [NCBI Gene 5641] {aka AEP, LGMN1, PRSC1}, ctnnb1 (catenin (cadherin-associated protein), beta 1) [NCBI Gene 30265] {aka ctnnb, id:ibd2058, wu:fb73e10, wu:fi81c06, wu:fk25h01}, LDLR (low density lipoprotein receptor) [NCBI Gene 3949] {aka LDLCQ2}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, MIR1290 (microRNA 1290) [NCBI Gene 100302276] {aka MIRN1290, hsa-mir-1290}, MGMT (O-6-methylguanine-DNA methyltransferase) [NCBI Gene 4255], Mgmt (O-6-methylguanine-DNA methyltransferase) [NCBI Gene 17314] {aka AGT, Agat}, NR1D2 (nuclear receptor subfamily 1 group D member 2) [NCBI Gene 9975] {aka BD73, EAR-1R, REVERBB, REVERBbeta, RVR}, Mdm4 (MDM4 regulator of p53) [NCBI Gene 17248] {aka 4933417N07Rik, Mdmx}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, OLFML3 (olfactomedin like 3) [NCBI Gene 56944] {aka HNOEL-iso, OLF44}, RET (ret proto-oncogene) [NCBI Gene 5979] {aka CDHF12, CDHR16, HSCR1, MEN2A, MEN2B, MTC1}, IL6R (interleukin 6 receptor) [NCBI Gene 3570] {aka CD126, HIES5, IL-1Ra, IL-6R, IL-6R-1, IL-6RA}, Arhgef2 (Rho/Rac guanine nucleotide exchange factor 2) [NCBI Gene 16800] {aka GEF, GEF-H1, GEFH1, LFP40, Lbcl1, Lfc}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, PIK3CG (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma) [NCBI Gene 5294] {aka IMD97, PI3CG, PI3K, PI3Kgamma, PIK3, p110gamma}, Rb1 (RB transcriptional corepressor 1) [NCBI Gene 19645] {aka Rb, Rb-1, p110-RB1, pRb, pp105}, PER1 (period circadian regulator 1) [NCBI Gene 5187] {aka PER, RIGUI, hPER}, Egfr (epidermal growth factor receptor) [NCBI Gene 13649] {aka 9030024J15Rik, Erbb, Errb1, Errp, Wa5, wa-2}, Lgmn (legumain) [NCBI Gene 19141] {aka AEP, Prsc1}
- **Diseases:** thromboembolic (MESH:D013923), ovarian cancer (MESH:D010051), sleep deprivation (MESH:D012892), lymphoma (MESH:D008223), retinoblastoma (MESH:D012175), breast cancer (MESH:D001943), GB tumour (MESH:D005909), astrocytoma (MESH:D001254), brain tissue damage (MESH:D017695), radiation necrosis (MESH:D011832), brain cancer (MESH:D001932), ocular and pulmonary toxicities (MESH:D005128), necrosis (MESH:D009336), Hematologic toxicity (MESH:D006402), Hypertension (MESH:D006973), tumorigenic (MESH:D002471), neutropenia (MESH:D009503), cerebral bleeding (MESH:D002543), metastasis (MESH:D009362), cytotoxicity (MESH:D064420), oedema (MESH:C536897), cardiovascular diseases (MESH:D002318), bone marrow suppression (MESH:D001855), fatigue (MESH:D005221), oncogenic (MESH:D000074723), tumorigenesis (MESH:D063646), cerebral oedema (MESH:D001929), leukopenia (MESH:D007970), medulloblastoma (MESH:D008527), hypoxia (MESH:D000860), circadian rhythm dysfunction (MESH:D021081), neurologic deficits (MESH:D009461), -related diseases (MESH:D000077733), seizures (MESH:D012640), sleep disorders (MESH:D012893), cervical cancer (MESH:D002583), injury to (MESH:D014947), Inflammation (MESH:D007249), headaches (MESH:D006261), Gliomas (MESH:D005910), multiple myeloma (MESH:D009101), insomnia (MESH:D007319), Grade 4 tumours (MESH:D009369)
- **Chemicals:** CCNU (MESH:D008130), Lipid (MESH:D008055), ATP (MESH:D000255), IR-820 (MESH:C541053), benzophenone (MESH:C047723), carboxymethylcellulose (MESH:D002266), polyamidoamine (MESH:C531249), glucose (MESH:D005947), magnesium (MESH:D008274), poly (beta-amino ester) (MESH:C507253), FA (MESH:D005492), Sev (MESH:D000077149), PB (MESH:D007854), DOX (MESH:D004317), Co-MION (-), nitrosourea (MESH:D009607), Melatonin (MESH:D008550), O6-methylguanine (MESH:C008449), CPP (MESH:D057846), thienopyrimidine (MESH:C476003), G4 (MESH:D004003), arginine (MESH:D001120), fatty acid (MESH:D005227), dexamethasone (MESH:D003907), SR9009 (MESH:C572451), gefitinib (MESH:D000077156), TMZ (MESH:D000077204), iron (MESH:D007501), glycogen (MESH:D006003), CHIR99021 (MESH:C473711), 5-HTP (MESH:D006916), PAA (MESH:C006903), Bortezomib (MESH:D000069286), procarbazine (MESH:D011344), Metformin (MESH:D008687), Bevacizumab (MESH:D000068258), HA (MESH:D006820), DEHP (MESH:D004051), GDP (MESH:D006153), Prussian Blue (MESH:C000170), VP (MESH:D000077362), oxygen (MESH:D010100), veliparib (MESH:C521013), platinum (MESH:D010984), GTP (MESH:D006160), Dp44mT (MESH:C539263), BCNU (MESH:D002330), ADP (MESH:D000244), guanine (MESH:D006147), Phosphatidylinositol phosphate (MESH:D018129), histidine (MESH:D006639), vincristine (MESH:D014750), paclitaxel (MESH:D017239), irinotecan (MESH:D000077146)
- **Species:** Drosophila melanogaster (fruit fly, species) [taxon 7227], Danio rerio (leopard danio, species) [taxon 7955], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Mus musculus (house mouse, species) [taxon 10090]
- **Cell lines:** LN229 — Homo sapiens (Human), Glioblastoma, Cancer cell line (CVCL_0393), HeLa — Homo sapiens (Human), Human papillomavirus-related cervical squamous cell carcinoma, Cancer cell line (CVCL_T292), T98G — Homo sapiens (Human), Glioblastoma, Cancer cell line (CVCL_0556), U87 — Homo sapiens (Human), Glioblastoma, Cancer cell line (CVCL_0022)

## Figures

6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12943994/full.md

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Source: https://tomesphere.com/paper/PMC12943994