Skin Science Fundamentals

Molecular Size & Penetration

Do your skincare ingredients actually reach your skin? The uncomfortable truth about absorption, the 500 Dalton rule, and why delivery systems matter.

January 26, 2026
9 min read
Collagen or Hyaluronic molecules from skin serum absorption to deep layer by skin cell. 3D rendering.

The Penetration Problem

Here's an uncomfortable truth: many of the ingredients you pay premium prices for never actually reach the layers of skin where they could make a difference. Your stratum corneum—designed to keep things out—doesn't discriminate between toxins and your $200 serum.

Blocked

Most large molecules sit on the surface

Partial

Some penetrate poorly without help

Effective

Small molecules with right delivery systems

The 500 Dalton Rule: Myth vs. Reality

What is the 500 Dalton Rule?

A Dalton (Da) measures molecular weight. The widely-cited "500 Dalton rule" suggests that molecules above 500 Da cannot penetrate intact skin. Below 500 Da? Fair chance of getting through. This rule comes from pharmacology research and has been adapted (sometimes misapplied) to skincare.

Why It's More Complicated

The 500 Da rule is a guideline, not an absolute. Other factors matter: lipophilicity (fat-solubility), charge, skin condition, and formulation. A damaged barrier lets larger molecules through. An optimized delivery system can ferry large molecules across.

Common Ingredients: Can They Penetrate?

Let's look at popular skincare ingredients and their molecular weights. The results might surprise you.

Can Penetrate (<500 Da)

Glycolic Acid 76 Da
Retinol 286 Da
Vitamin C (L-AA) 176 Da
Niacinamide 122 Da
Salicylic Acid 138 Da
Caffeine 194 Da

Cannot Penetrate (>500 Da)

Hyaluronic Acid ~1,000,000 Da
Collagen ~300,000 Da
Elastin ~70,000 Da
Most Peptides 500-5,000 Da
EGF (Growth Factor) ~6,000 Da
Most Plant Extracts Variable, often large

Wait—Does Hyaluronic Acid Actually Work?

Yes, but not how you think. Standard HA sits on skin's surface, drawing moisture from the air (good) or from deeper skin layers (bad in dry climates). It works as a humectant on the surface, not by penetrating.

Low molecular weight HA (under 50,000 Da) can penetrate slightly better, and hydrolyzed HA fragments are even smaller. But even these don't reach the dermis where your body produces HA naturally.

Delivery Systems: How Brands Overcome the Barrier

Smart formulation can bypass the 500 Dalton limitation. Here's how advanced delivery systems work—and which ones actually have evidence behind them.

Liposomes

Tiny spheres made of lipids (fats) that encapsulate ingredients. Because they're lipid-based, they can merge with your skin's lipid matrix and release their cargo deeper.

Evidence: Strong Used for: Vitamin C, Retinol, Peptides

Nanoparticles & Nanosomes

Even smaller than liposomes (under 100nm), nanoparticles can penetrate deeper. They're used to deliver sunscreen filters, antioxidants, and anti-aging ingredients.

Evidence: Moderate-Strong Used for: Zinc Oxide, CoQ10

Microencapsulation

Ingredients are coated in a protective shell that breaks down on skin contact or over time. This protects unstable ingredients (like retinol) and allows controlled release.

Evidence: Strong Used for: Retinol, Vitamin E

Penetration Enhancers

Ingredients that temporarily disrupt the stratum corneum to let other ingredients through. Examples: propylene glycol, ethanol, oleic acid, certain surfactants.

Evidence: Strong but trade-offs Caution: Can cause irritation

What This Means For Your Routine

  • Don't pay premium for collagen or elastin in serums—they can't penetrate. Take collagen internally if you want to boost levels.
  • Look for delivery systems in products with large molecules (peptides, growth factors). "Liposomal" or "encapsulated" formulas are worth the extra cost.
  • Small molecules work—retinol, niacinamide, AHAs, vitamin C. These are proven to penetrate effectively.
  • Surface benefits still matter—HA and collagen on the surface still hydrate and protect, just not by "rebuilding" your skin.

Disclaimer: This article is for educational purposes only and is not intended as medical advice. The information presented is based on generally accepted skincare science, but individual results may vary. Always consult a board-certified dermatologist or healthcare provider before making changes to your skincare routine, especially if you have existing skin conditions.

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