Multi-mechanistic mitochondria-mediated N-methylated YKWYYRGAA-decorated nano-chitosan conjugate carrier for treatment of NRAS-mutant-harbouring lung carcinoma

Yazid Zaiki; Chin Fei Chee; Lucia Ageitos; Idanawati Naharudin; Badrul Hisyam Zainudin; Lek Mun Leong; Jaime Rodriguez González; Carlos Jimenez; Chee Yuen Gan; Daniela Traini; Tin Wui Wong

doi:10.1016/j.carbpol.2026.125423

Multi-mechanistic mitochondria-mediated N-methylated YKWYYRGAA-decorated nano-chitosan conjugate carrier for treatment of NRAS-mutant-harbouring lung carcinoma

Yazid Zaiki, Chin Fei Chee, Lucia Ageitos, Idanawati Naharudin, Badrul Hisyam Zainudin, Lek Mun Leong, Jaime Rodriguez González, Carlos Jimenez, Chee Yuen Gan, Daniela Traini, Tin Wui Wong

Macquarie Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

Cell targeting/permeabilization, organelle/biochemical pathway regulation, and drug resistance/metastasis/immunological expressions are considerations to advance cancer nanomedicine design. This study modulated mitochondria-targeting YKWYYRGAA (P1) peptide, into a multifunctional excipient via N -methylation and N -dimethylation, to synergise nano-chitosan conjugate in drug delivery and non-small cell lung cancer treatment. The spray-dried chitosan nanoparticles developed from P1, N- methylated YKWYYRGAA (P2) and N -dimethylated YKWYYRGAA (P3) were subjected to physicochemical testing, NRAS-mutated H1299 cell permeability/cytotoxicity/apoptosis and cell cycle arrest/drug resistance/metastasis/immunomodulation assessment, and in vivo pharmacokinetics/pharmacodynamics investigations. Methylated P2 increased cancer cell permeability/intracellular drug/nanoparticle uptake/drug targeting via sustained- and pH-stimuli responsive release and cytotoxicity unlike P1 and P3 which were ceased at membrane interface by excessive ionic/hydrophobic interactions. P2-grafted nanochitosan induced mitochondria-mediated apoptosis with minimal necrosis via ROS activation and FasL-linked death. It suppressed mTOR/MAPK signalling overcoming EGFR-resistance/EGFR mutation-independent pathways in tumorigenesis. It mitigated drug resistance via downregulating P-gp (efflux receptor) and GSTP1 (degrading enzyme) expressions, and epithelial-mesenchymal transition via interplay of E-cadherin against N-cadherin/snail/twist 1/vimentin/ezrin/MMP9 with MICA/ULBP1 suppression to reduce immunological lung tissue lysis. The inhaled P2-grafted nanochitosan provided a positive lung cancer recovery with reduced systemic exposure and hematological/biochemical toxicities. Single instead of dimethylation of YKWYYRGAA promoted the cascades of inter-dependent anti-cancer activities and efficacy of nanochitosan.

Original language	English
Article number	125423
Pages (from-to)	1-19
Number of pages	19
Journal	Carbohydrate Polymers
Volume	386
DOIs	https://doi.org/10.1016/j.carbpol.2026.125423
Publication status	Accepted/In press - 10 May 2026

Keywords

Cancer
Chitosan
Mitochondria
Nanoparticles
Peptide
YKWYYRGAA

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10.1016/j.carbpol.2026.125423

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Zaiki, Y., Chee, C. F., Ageitos, L., Naharudin, I., Zainudin, B. H., Leong, L. M., Rodriguez González, J., Jimenez, C., Gan, C. Y., Traini, D., & Wong, T. W. (Accepted/In press). Multi-mechanistic mitochondria-mediated N-methylated YKWYYRGAA-decorated nano-chitosan conjugate carrier for treatment of NRAS-mutant-harbouring lung carcinoma. Carbohydrate Polymers, 386, 1-19. Article 125423. https://doi.org/10.1016/j.carbpol.2026.125423

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title = "Multi-mechanistic mitochondria-mediated N-methylated YKWYYRGAA-decorated nano-chitosan conjugate carrier for treatment of NRAS-mutant-harbouring lung carcinoma",

abstract = "Cell targeting/permeabilization, organelle/biochemical pathway regulation, and drug resistance/metastasis/immunological expressions are considerations to advance cancer nanomedicine design. This study modulated mitochondria-targeting YKWYYRGAA (P1) peptide, into a multifunctional excipient via N -methylation and N -dimethylation, to synergise nano-chitosan conjugate in drug delivery and non-small cell lung cancer treatment. The spray-dried chitosan nanoparticles developed from P1, N- methylated YKWYYRGAA (P2) and N -dimethylated YKWYYRGAA (P3) were subjected to physicochemical testing, NRAS-mutated H1299 cell permeability/cytotoxicity/apoptosis and cell cycle arrest/drug resistance/metastasis/immunomodulation assessment, and in vivo pharmacokinetics/pharmacodynamics investigations. Methylated P2 increased cancer cell permeability/intracellular drug/nanoparticle uptake/drug targeting via sustained- and pH-stimuli responsive release and cytotoxicity unlike P1 and P3 which were ceased at membrane interface by excessive ionic/hydrophobic interactions. P2-grafted nanochitosan induced mitochondria-mediated apoptosis with minimal necrosis via ROS activation and FasL-linked death. It suppressed mTOR/MAPK signalling overcoming EGFR-resistance/EGFR mutation-independent pathways in tumorigenesis. It mitigated drug resistance via downregulating P-gp (efflux receptor) and GSTP1 (degrading enzyme) expressions, and epithelial-mesenchymal transition via interplay of E-cadherin against N-cadherin/snail/twist 1/vimentin/ezrin/MMP9 with MICA/ULBP1 suppression to reduce immunological lung tissue lysis. The inhaled P2-grafted nanochitosan provided a positive lung cancer recovery with reduced systemic exposure and hematological/biochemical toxicities. Single instead of dimethylation of YKWYYRGAA promoted the cascades of inter-dependent anti-cancer activities and efficacy of nanochitosan.",

keywords = "Cancer, Chitosan, Mitochondria, Nanoparticles, Peptide, YKWYYRGAA",

author = "Yazid Zaiki and Chee, \{Chin Fei\} and Lucia Ageitos and Idanawati Naharudin and Zainudin, \{Badrul Hisyam\} and Leong, \{Lek Mun\} and \{Rodriguez Gonz{\'a}lez\}, Jaime and Carlos Jimenez and Gan, \{Chee Yuen\} and Daniela Traini and Wong, \{Tin Wui\}",

year = "2026",

month = may,

day = "10",

doi = "10.1016/j.carbpol.2026.125423",

language = "English",

volume = "386",

pages = "1--19",

journal = "Carbohydrate Polymers",

issn = "0144-8617",

publisher = "Elsevier",

}

Zaiki, Y, Chee, CF, Ageitos, L, Naharudin, I, Zainudin, BH, Leong, LM, Rodriguez González, J, Jimenez, C, Gan, CY, Traini, D & Wong, TW 2026, 'Multi-mechanistic mitochondria-mediated N-methylated YKWYYRGAA-decorated nano-chitosan conjugate carrier for treatment of NRAS-mutant-harbouring lung carcinoma', Carbohydrate Polymers, vol. 386, 125423, pp. 1-19. https://doi.org/10.1016/j.carbpol.2026.125423

TY - JOUR

T1 - Multi-mechanistic mitochondria-mediated N-methylated YKWYYRGAA-decorated nano-chitosan conjugate carrier for treatment of NRAS-mutant-harbouring lung carcinoma

AU - Zaiki, Yazid

AU - Chee, Chin Fei

AU - Ageitos, Lucia

AU - Naharudin, Idanawati

AU - Zainudin, Badrul Hisyam

AU - Leong, Lek Mun

AU - Rodriguez González, Jaime

AU - Jimenez, Carlos

AU - Gan, Chee Yuen

AU - Traini, Daniela

AU - Wong, Tin Wui

PY - 2026/5/10

Y1 - 2026/5/10

N2 - Cell targeting/permeabilization, organelle/biochemical pathway regulation, and drug resistance/metastasis/immunological expressions are considerations to advance cancer nanomedicine design. This study modulated mitochondria-targeting YKWYYRGAA (P1) peptide, into a multifunctional excipient via N -methylation and N -dimethylation, to synergise nano-chitosan conjugate in drug delivery and non-small cell lung cancer treatment. The spray-dried chitosan nanoparticles developed from P1, N- methylated YKWYYRGAA (P2) and N -dimethylated YKWYYRGAA (P3) were subjected to physicochemical testing, NRAS-mutated H1299 cell permeability/cytotoxicity/apoptosis and cell cycle arrest/drug resistance/metastasis/immunomodulation assessment, and in vivo pharmacokinetics/pharmacodynamics investigations. Methylated P2 increased cancer cell permeability/intracellular drug/nanoparticle uptake/drug targeting via sustained- and pH-stimuli responsive release and cytotoxicity unlike P1 and P3 which were ceased at membrane interface by excessive ionic/hydrophobic interactions. P2-grafted nanochitosan induced mitochondria-mediated apoptosis with minimal necrosis via ROS activation and FasL-linked death. It suppressed mTOR/MAPK signalling overcoming EGFR-resistance/EGFR mutation-independent pathways in tumorigenesis. It mitigated drug resistance via downregulating P-gp (efflux receptor) and GSTP1 (degrading enzyme) expressions, and epithelial-mesenchymal transition via interplay of E-cadherin against N-cadherin/snail/twist 1/vimentin/ezrin/MMP9 with MICA/ULBP1 suppression to reduce immunological lung tissue lysis. The inhaled P2-grafted nanochitosan provided a positive lung cancer recovery with reduced systemic exposure and hematological/biochemical toxicities. Single instead of dimethylation of YKWYYRGAA promoted the cascades of inter-dependent anti-cancer activities and efficacy of nanochitosan.

AB - Cell targeting/permeabilization, organelle/biochemical pathway regulation, and drug resistance/metastasis/immunological expressions are considerations to advance cancer nanomedicine design. This study modulated mitochondria-targeting YKWYYRGAA (P1) peptide, into a multifunctional excipient via N -methylation and N -dimethylation, to synergise nano-chitosan conjugate in drug delivery and non-small cell lung cancer treatment. The spray-dried chitosan nanoparticles developed from P1, N- methylated YKWYYRGAA (P2) and N -dimethylated YKWYYRGAA (P3) were subjected to physicochemical testing, NRAS-mutated H1299 cell permeability/cytotoxicity/apoptosis and cell cycle arrest/drug resistance/metastasis/immunomodulation assessment, and in vivo pharmacokinetics/pharmacodynamics investigations. Methylated P2 increased cancer cell permeability/intracellular drug/nanoparticle uptake/drug targeting via sustained- and pH-stimuli responsive release and cytotoxicity unlike P1 and P3 which were ceased at membrane interface by excessive ionic/hydrophobic interactions. P2-grafted nanochitosan induced mitochondria-mediated apoptosis with minimal necrosis via ROS activation and FasL-linked death. It suppressed mTOR/MAPK signalling overcoming EGFR-resistance/EGFR mutation-independent pathways in tumorigenesis. It mitigated drug resistance via downregulating P-gp (efflux receptor) and GSTP1 (degrading enzyme) expressions, and epithelial-mesenchymal transition via interplay of E-cadherin against N-cadherin/snail/twist 1/vimentin/ezrin/MMP9 with MICA/ULBP1 suppression to reduce immunological lung tissue lysis. The inhaled P2-grafted nanochitosan provided a positive lung cancer recovery with reduced systemic exposure and hematological/biochemical toxicities. Single instead of dimethylation of YKWYYRGAA promoted the cascades of inter-dependent anti-cancer activities and efficacy of nanochitosan.

KW - Cancer

KW - Chitosan

KW - Mitochondria

KW - Nanoparticles

KW - Peptide

KW - YKWYYRGAA

UR - https://www.scopus.com/pages/publications/105038396236

U2 - 10.1016/j.carbpol.2026.125423

DO - 10.1016/j.carbpol.2026.125423

M3 - Article

C2 - 42230031

SN - 0144-8617

VL - 386

SP - 1

EP - 19

JO - Carbohydrate Polymers

JF - Carbohydrate Polymers

M1 - 125423

ER -

Multi-mechanistic mitochondria-mediated N-methylated YKWYYRGAA-decorated nano-chitosan conjugate carrier for treatment of NRAS-mutant-harbouring lung carcinoma

Abstract

Keywords

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