Recent progress in the development of nanomaterials targeting multiple cancer metabolic pathways: a review of mechanistic approaches for cancer treatment

Cancer incidence and mortality remain high globally, with metabolic reprogramming recognized as a hallmark of cancer that supports uncontrolled growth, survival, and metastasis. Conventional therapies (chemotherapy, radiotherapy) often suffer from poor specificity, significant toxicity, drug resistance, recurrence, and metastasis. Metabolism-based therapies have shown a therapeutic window (e.g., nucleotide biosynthesis), and recent insights into pathways such as polyamine metabolism and PI3K–mTORC1 have spurred novel approaches and combinational strategies. Nanoparticles (NPs) offer unique physicochemical properties enabling targeted delivery, controlled release, improved pharmacokinetics, and reduced off-target effects. This review aims to synthesize recent advances in nanomaterials that target diverse cancer metabolic pathways (glucose, amino acids, lipids, redox), highlighting mechanisms, therapeutic benefits over conventional treatments, challenges to clinical translation, and future directions.

The paper reviews: (1) the metabolic rewiring in cancer driven by oncogenes/tumor suppressors affecting glucose and glutamine metabolism (e.g., Ras, c-Myc, PI3K/AKT, p53, LKB1–AMPK); (2) tumor nutrient scavenging under stress (macropinocytosis of proteins, collagen uptake for proline, albumin as nutrient source, extracellular lipid scavenging, acetate utilization via ACSS2); (3) NP-enabled targeting strategies (passive EPR, active ligand-mediated targeting) and approved/clinical nanoformulations (e.g., Genexol-PM) demonstrating improved tissue accumulation and tolerability; (4) diagnostic/therapeutic NP platforms including SPIONs for hyperthermia, photothermal/photodynamic nanomaterials, exosome/liposome/dendrimer/polymeric carriers for nucleic acids; (5) metabolism-targeted nanotherapies across pathways: glycolysis/GLUT/PDK1; mTOR; Hedgehog/GLI; ATP suppression via mitochondrial NO; ROS-based therapies (PDT/CDT) and defect-engineered quantum dots; (6) tumor metabolic heterogeneity and combination strategies to target proliferative (glutamine-dependent) and hypoxic (glycolysis-dependent) cancer cell subpopulations. The review integrates preclinical and some clinical examples to map mechanistic links between NP design and metabolic pathway modulation.

This is a narrative review that synthesizes and discusses recent preclinical and clinical literature on nanomaterials targeting cancer metabolism. The article does not specify a systematic search strategy, databases, inclusion/exclusion criteria, or quantitative meta-analytic methods.

- Cancer metabolic rewiring and vulnerabilities: - Oncogenic drivers (Ras, c-Myc, PI3K/AKT, LKB1–AMPK) enhance glucose/glutamine uptake, glycolysis, glutaminolysis, and lipogenesis; tumors also scavenge extracellular macromolecules and lipids under nutrient stress; acetate metabolism via ACSS2 supports tumor growth. - Advantages of NP-based delivery over conventional therapy: - Enhanced permeability and retention (EPR) and active targeting improve tumor accumulation, reduce off-target toxicity, protect drugs from degradation, increase solubility/half-life, enable controlled release, and can overcome resistance. - Example: Genexol-PM (paclitaxel micelles) achieved 2–3× higher tissue concentrations in tumors vs. healthy tissues and a maximum tolerated dose ~3× higher in mice; approved in South Korea for MBC; ongoing trials elsewhere. - Verteporfin solid-lipid NPs for ovarian cancer: free drug at 2 mg/kg caused toxicity/death, whereas NP formulation showed no toxicity at 8 mg/kg with significant tumor suppression upon laser activation. - Targeting glycolysis/glucose metabolism: - PDK1 inhibition (JX06-NPs) combined with metformin suppressed glycolysis and OXPHOS respectively, reducing tumor growth in endometrial cancer diabetic mouse models; JX06-NPs showed superior in vitro inhibition vs. free JX06 and tumor accumulation in vivo. - Addressing metabolic heterogeneity (glucose/glutamine): - BPTES (glutaminase inhibitor) in PLGA-PEG NPs improved PK and antitumor effects in patient-derived pancreatic tumor models; combination with metformin (targets hypoxic, glycolysis-dependent cells) significantly enhanced efficacy over monotherapies. - ATP suppression and drug resistance reversal: - Acid-activated, mitochondria-targeted NO nanocarriers decreased ATP, impaired P-glycoprotein activity, reduced tumor-derived microvesicles, and inhibited metastasis in models, enhancing therapeutic response. - mTOR pathway modulation: - Multiple NPs demonstrate capacity to modulate/inhibit mTOR signaling, offering potential across cancers, though clinical success with mTOR inhibitors remains limited; combination and dosing strategies with NPs may optimize responses. - Hedgehog (Hh) signaling targeting: - Thymoquinone-loaded, PSMA-aptamer-conjugated PBM-NPs selectively targeted docetaxel-resistant prostate cancer, inhibiting SHH/GLI signaling and ABC transporter-mediated chemoresistance. - ROS/oxidative stress-based strategies (PDT/CDT): - Nostoc-mediated AgNPs induced ROS, caspase-3/p53 activation, mTOR suppression, and apoptosis in multiple cancer lines. - PEG–AuNPs–RNase A increased ROS and apoptosis, reducing SW-480 colorectal cancer viability. - Alginate hydrogels co-loaded with cisplatin and AuNPs increased intracellular ROS 4.4-fold, upregulated Bax, and downregulated Bcl-2 in KB cells. - Carbonized hemin NPs boosted PDT efficacy via improved ROS generation, GSH depletion, and hypoxia relief, reducing tumor size in mice with good biocompatibility. - Ce6-loaded manganese ferrite NP–anchored mesoporous silica NPs relieved hypoxia via O2 evolution and enhanced PDT to eradicate U87MG cells. - Sulfur-defect engineered CoSx quantum dots combined photothermal with Fenton-like CDT, increasing •OH generation and anticancer efficacy; ultrasmall, biodegradable QDs reduced systemic accumulation. - Overall: NP platforms can precisely target and modulate multiple metabolic nodes/pathways, enable synergistic combinations (e.g., glycolysis + glutaminolysis; PDT + CDT; mitochondrial ATP suppression + chemotherapy), and demonstrate improved efficacy/safety profiles in preclinical models.

By mapping cancer’s metabolic dependencies (glycolysis, glutaminolysis, lipid/acetate utilization, redox balance) to nanoparticle-enabled delivery and catalytic functions, the review shows how nanomaterials can more selectively exploit tumor metabolism than conventional agents. Targeted NP formulations enhance intratumoral drug concentrations, overcome efflux-mediated resistance via ATP suppression or transporter inhibition, and enable multimodal therapies (e.g., PDT/CDT/PTT combinations) that intensify oxidative stress within tumors while sparing normal tissue. Addressing metabolic heterogeneity with combinational NP strategies (e.g., glutaminase inhibition plus metformin) targets both proliferative and hypoxic cell populations, improving overall tumor control. Despite promising preclinical outcomes, translation requires careful consideration of NP–biological interactions (protein corona, MPS uptake), tumor microenvironment (hypoxia, acidity), and interpatient variability. The findings collectively support the central hypothesis that nanotechnology can be leveraged to target multiple cancer metabolic pathways for superior specificity and efficacy compared with traditional treatments.

Nanomaterials provide versatile platforms to target diverse cancer metabolic pathways, enabling improved delivery, specificity, controlled release, and combinational regimens that counteract resistance, recurrence, and metastasis. Preclinical evidence demonstrates meaningful benefits across pathways including glycolysis/PDK1, glutaminase, mTOR, Hedgehog/GLI, mitochondrial ATP production, and ROS-based modalities (PDT/CDT/PTT). Several nanomedicines are clinically approved or in trials, underscoring translational potential. However, broad clinical adoption requires resolving toxicity, stability, immune recognition (MPS), and study design challenges, and developing better in vitro/in vivo models (including metastasis models). Future research should: (1) optimize active targeting and surface engineering to reduce off-target effects and MPS clearance; (2) personalize NP therapies based on tumor metabolic phenotypes; (3) integrate nanomedicine with immunotherapy and gene therapy; and (4) develop smart, multifunctional nanostructures for early detection and multi-target treatment.

- The article is a narrative review without a defined systematic methodology, risking selection bias. - Most evidence cited is preclinical (cell lines, mice), limiting generalizability to humans. - Key translational hurdles remain: NP toxicity, stability, protein corona/MPS uptake, immune responses, and variability in EPR effect. - Current in vitro models inadequately recapitulate in vivo tumor–NP interactions; better models of metastasis and tumor heterogeneity are needed. - Limited data on long-term safety, biodistribution, and clearance for many nanoplatforms.