When proteins are covalently modified or otherwise damaged they can misfold, oligomerize, and form amyloid fibrils; the intermediate oligomeric species and associated degradation products are often the most cytotoxic. This review summarizes the chemistry of adduction (with emphasis on amino-acid targets), downstream biochemical pathways that convert modified proteins into toxic species, specific toxic products of misfolding and degradation, and dietary patterns/food combinations likely to favor adduct formation and amyloidogenesis. 

Defining adduction and its chemical underpinnings

In simple terms, adduction in a biochemical context refers to a process where a harmful molecule (called an electrophile) attaches itself to a part of your body’s molecules, like proteins, DNA, or fats. These harmful molecules can come from various sources, such as pollution, cigarette smoke, or even certain foods and chemicals.

When the electrophile forms a bond with your body’s molecules, it changes the way those molecules behave. This bond is permanent, meaning it can’t easily be undone. The molecule now has a different structure, charge, or reactivity. This can be dangerous because it can alter how important molecules in your body function. For example:

Because adducts are chemically stable, (relative to noncovalent associations) they therefore can permanently alter structure, charge, or reactivity of the target.

Common sources of adduct-forming electrophiles:

• Lipid peroxidation products: The products of lipid peroxidation—4-HNE, MDA, and acrolein—are harmful because they can lead to cellular damage, inflammation, and oxidative stress, which are associated with various chronic diseases, including cancer, cardiovascular diseases, neurodegenerative diseases, and respiratory issues. Their ability to damage DNA, proteins, and lipids compromises cellular integrity and function, contributing to aging and the onset of degenerative diseases. Consequently, reducing oxidative stress and preventing lipid peroxidation is critical for maintaining health and preventing disease. The DNA mutations caused by these compounds may activate oncogenes (genes that promote cancer) or deactivate tumor suppressor genes (genes that prevent cancer).
• Reactive carbonyls from glycation: methylglyoxal and other dicarbonyls formed during high-sugar metabolism and the Maillard reaction. The accumulation of AGEs can damage proteins, affecting their normal function and stability. This can impair vital cellular processes, such as enzyme activity, receptor signaling, and tissue integrity. For example, when AGEs form on collagen, it leads to tissue stiffening, contributing to age-related diseases like atherosclerosis and kidney damage.
• Reactive oxygen/nitrogen species derivatives: chlorinated and nitrated species that produce electrophilic fragments. Chlorinated and nitrated species—by-products of oxidative and nitrosative stress—are harmful to the human body because they generate electrophilic fragments that damage proteins, lipids, and DNA. This damage leads to genetic mutations, inflammation, endothelial dysfunction, immune overreaction, and accelerated aging, all of which contribute to the development of chronic diseases like cancer, cardiovascular diseases, neurodegeneration, and autoimmune disorders. Reducing exposure to oxidative and nitrosative stress, through dietary and lifestyle changes, as well as controlling inflammation, can help mitigate these harmful effects and promote better long-term health.
• Exogenous xenobiotics after metabolic activation (e.g., nitrosamines, some drug metabolites). xenobiotics can damage DNA, proteins, and lipids, leading to mutations, organ dysfunction, inflammation, and cancer. Understanding the toxicology of these compounds is crucial for minimizing exposure, whether through dietary choices, avoiding environmental pollutants, or using medications responsibly. Nitrosamines are a group of chemical compounds formed when nitrites (often found in processed meats) react with amines in the body, particularly under acidic conditions, such as in the stomach. Once consumed, nitrosamines can be metabolized into highly reactive compounds. These activated nitrosamines are known to be carcinogenic (cancer-causing) because they can damage DNA by forming DNA adducts. These adducts are abnormal chemical bonds between the xenobiotic and the DNA molecule, which can lead to mutations and genomic instability, major drivers of cancer development.

Toxic products derived from misfolding and degradation

Naskar, S.; Gour, N. Realization of Amyloid like Aggregation as a Common Cause for the Pathogenesis in Diseases. Preprints 2023, 2023051547. 

• Soluble oligomers (prefibrillar species): Often more cytotoxic than mature fibrils; can disrupt membranes, form pore-like structures, and dysregulate calcium.
• Amyloid fibrils/plaques: Highly ordered β-sheet-rich fibrils that deposit extracellularly (e.g., Aβ in Alzheimer’s) or intracellularly (e.g., α-synuclein in Parkinson’s).
• Protein carbonyls: Oxidatively modified, often irreversible carbonyl adducts; markers of oxidative damage and contributors to dysfunction.
• Advanced Glycation End Products (AGEs): Crosslinked protein–sugar adducts that are pro-inflammatory and can seed crosslinking between proteins.
• Lipid–protein crosslinks: e.g., 4-HNE adducts that covalently attach lipid-derived aldehydes to proteins, changing membrane interactions and trafficking.
• Truncated peptide fragments: Proteolytic fragments of adducted proteins can be aggregation-prone and seed amyloid formation.
• Neo-epitopes: Modified proteins may be recognized as non-self and initiate autoimmune responses.

Downstream cellular effects include oxidative stress amplification, mitochondrial dysfunction, impaired proteostasis, chronic inflammation (via NLRP3 inflammasome and microglial activation in the CNS), and cell death pathways.

LNPs, aldehydes, and the quoted passage — verbatim insertion

From Dr. McMillan's Substack:

"Evidence has now been brought forward by Christie Grace. In her review of the science, she highlights a critical blind spot: lipid nanoparticles (LNPs) are not chemically inert. They break down into reactive fragments that can permanently bind to RNA, DNA, or proteins. These permanent chemical scars are called adducts. And if they occur in the body as they do in the lab, they represent a problem that no amount of rebranding or reassurance can erase. The mechanism is clear: as LNPs degrade, they generate aldehydes and peroxides. These molecules are highly reactive, forming covalent adducts with nucleic acids and proteins. In Moderna’s own study, RNA bases were shown to form adducts — particularly adenine — with rates increasing at warmer temperatures. At −20 °C, the damage slowed. At body temperature, 37 °C, the chemistry accelerated.

Adducted RNA does not behave normally. It may fail to translate at all, or it may produce truncated fragments that misfold. If proteins or DNA are caught in this chemistry, the consequences could include misfolding, mutagenesis, or autoimmune activation against newly distorted shapes. These aren’t fringe ideas — they are well-established outcomes of adduct biology in toxicology. Here is where the story takes a darker turn. The International Council for Harmonisation (ICH) M7 guidelines already recognize that genotoxic impurities are unacceptable in pharmaceuticals, even at trace levels. Entire drug classes have been withdrawn because of them. By those standards, LNP-derived aldehydes should have been investigated with urgency. But that never happened.The truth is stark: if lipid nanoparticles are forming adducts inside the body, the mRNA platform may not just be risky — it may be fundamentally untenable."

The chemistry described is biochemically plausible in principle. Lipid peroxidation yields electrophilic aldehydes (4-HNE, MDA, acrolein). These species are well known to form covalent adducts with protein side chains (Cys, Lys, His) and nucleic acids. Aldehyde chemistry accelerates at higher temperature; many chemical reactions are temperature-sensitive. Adduction of RNA bases or protein residues can plausibly:

(a) interfere with translation,

(b) produce truncated or misfolded proteins, and

(c) create neo-epitopes that the immune system could recognize. These are well-documented in toxicology for many electrophiles.

Dietary factors and food combinations that promote adduct formation and amyloidogenesis

Adduct formation and amyloid formation are influenced by systemic metabolic state, diet-derived reactive species, and postprandial chemistry. The following dietary patterns and combinations are mechanistically linked to increased adduct load and amyloid risk:

1. High sugar + protein (promotes glycation and AGE formation)

Mechanism: reducing sugars and dicarbonyl intermediates (methylglyoxal, glyoxal) react with Lys and Arg to produce Schiff bases and AGEs; AGEs crosslink proteins, increase hydrophobicity, and impair proteasomal degradation. Examples: sweetened high-protein beverages, high simple sugar intake with protein meals, frequent consumption of high-glycemic load foods.

2. High heat cooking of protein + fats (Maillard products & lipid oxidation)

Mechanism: grilling/frying at high temperatures gives rise to both Maillard reaction products (AGEs) and lipid oxidation products (aldehydes such as 4-HNE). Combined, these produce protein crosslinks and hydrophobic adducts that seed aggregation. Examples: charred meats with sugary glazes, deep-fried foods, repeat-heated oils.

3. Processed meats and nitrosamine-forming foods

Mechanism: nitrosation and heterocyclic amine formation during processing/cooking yield electrophiles that can alkylate nucleophiles on proteins and DNA. Examples: processed, cured meats; bacon and sausages especially when pan-fried.

4. Diets that produce chronic oxidative stress

Mechanism: diets high in saturated fat and refined carbohydrates promote systemic oxidative stress and inflammation, increasing in situ lipid peroxidation and formation of reactive aldehydes. Examples: chronic overconsumption of high-fat/ high-sugar Western patterns.

5. Low antioxidant intake (insufficient polyphenols, carotenoids, vitamins)

Mechanism: antioxidants quench radical initiation steps that produce lipid peroxides and carbonyls. Low intake removes a defense against adduct formation. Examples: diets poor in fruits, vegetables, legumes, tea, and other sources of polyphenols.

Specific food combinations to avoid if the goal is to minimize adducts/AGEs

• Sugary drinks consumed with high-protein/high-fat fried meals (high sugar + heat + fat).
• Meat heavily charred and consumed with high-simple-sugar sauces (elevates both AGEs and lipid peroxidation products).
• Repeatedly reheated cooking oils (accumulate peroxides and aldehydes).

Molecular Routes by Which Adduct Formation Can Seed Amyloidogenesis

Adduct formation can trigger amyloidogenesis through several interconnected molecular mechanisms. When adduction occurs, it destabilizes the native protein fold, exposing hydrophobic β-strand segments that are normally buried within the protein structure. These exposed regions are highly prone to aggregation and serve as nucleation sites for oligomerization. Additionally, covalent crosslinks formed by advanced glycation end products (AGEs) or lipid-derived aldehydes create stable oligomers that resist protease degradation and act as seeds for fibril formation. In some cases, adducted RNA or impaired translational fidelity may theoretically produce truncated or misfolded proteins with heightened aggregation propensity. The problem is further compounded when adduction affects ubiquitination sites or impairs proteasome function, leading to the accumulation of aggregates that would normally be cleared. Perhaps most concerningly, adducted proteins may promote heterologous cross-seeding, where modified proteins catalyze the aggregation of different amyloidogenic proteins—for instance, lipid-adducted proteins potentially seeding the formation of amyloid-beta or alpha-synuclein aggregates.

Experimental Approaches to Demonstrate the Adduct-to-Amyloid Pathway In Vivo

Testing this hypothesis requires a multi-faceted experimental strategy. Adductomics—using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)—enables precise detection of specific adducts such as lysine-malondialdehyde (Lys-MDA), cysteine-4-hydroxynonenal (Cys-4-HNE), and nucleic acid adducts in tissues following exposure. Stable isotope labeling of lipids or lipid nanoparticle (LNP) components allows researchers to trace their breakdown products and map adduct formation pathways. Functional readouts provide critical insights into downstream consequences, including translation assays to assess mRNA integrity, measurement of truncated protein products, and proteasome activity assays to evaluate clearance capacity. Aggregation assays—including thioflavin T (ThT) binding, electron microscopy, and seeding experiments—can directly detect amyloid formation from exposed proteins. Finally, comprehensive in vivo toxicology studies incorporating dose-response relationships, biodistribution analysis, immune profiling for neo-epitope responses, and mutagenicity or genotoxicity panels are essential for understanding the biological significance of these processes.

Concluding Summary

Adduct formation is a chemically well-defined process with well-documented capacity to alter protein structure and function. Covalent modification of susceptible amino-acid residues (Cys, Lys, His, Arg, Tyr) and nucleic-acid bases can destabilize proteome integrity and accelerate pathways that lead to toxic oligomers and amyloid fibrils. Dietary patterns that increase glycation, lipid peroxidation, or oxidative stress plausibly raise the body’s adduct burden and therefore the probability of proteostasis failure. Hypotheses that particular biomedical formulations (e.g., LNPs) may generate adduct-forming fragments are chemically plausible and therefore merit rigorous analytical and in vivo testing; however, showing plausibility is distinct from demonstrating clinical risk — which requires direct experimental evidence, dose–response analysis, and epidemiology.

References 

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3. Esterbauer, H., Schaur, R. J. & Zollner, H. Chemistry and biochemistry of 4-hydroxynonenal, malondialdehyde and related aldehydes. Free Radical Biology & Medicine 11, 81–128 (1991).
4. Singh, R., Barden, A., Mori, T. & Beilin, L. Advanced glycation end-products: a review. Diabetologia 44, 129–146 (2001).
5. Knowles, T. P. J., Vendruscolo, M. & Dobson, C. M. The amyloid state and its association with protein misfolding diseases. Nature Reviews Molecular Cell Biology 15, 384–396 (2014).