A first dose of PEGylated lipid nanoparticle (LNP) is normally "stealthed" against the reticuloendothelial system. But PEG itself is weakly immunogenic: it primes B-cells that secrete anti-PEG IgM (peaking ~5–7 days later). If a second LNP dose arrives while that titer is high, the antibodies opsonize the particles, fix complement, and Kupffer macrophages in the liver sinusoids clear them within minutes — the "Accelerated Blood Clearance" (ABC) phenomenon. This is the main reason repeat-dose CRISPR/mRNA-LNP therapies must manage redosing intervals or use PEG-alternative coatings.
k_clear(Ab) = k_base·(1 − stealth) + k_immune·Kupffer·Ab^2 / (Ab^2 + Kd^2)
k_total = k_clear + k_target (competing first-order removal)
C_blood(t) = C0 · e^(−k_total·t) (intact, still-circulating dose)
Delivered(t)= C0 · [k_target / k_total] · (1 − e^(−k_total·t))
t½ = ln(2) / k_total
- Anti-PEG antibody titer — pre-existing immunity from a prior LNP/mRNA-LNP exposure; drives complement-mediated opsonization via a Hill-type dose-response (Kd = 40 AU).
- PEG stealth coating — reduces baseline non-immune reticuloendothelial uptake, but cannot fully protect once specific antibodies are bound.
- Kupffer activity — liver macrophage phagocytic state; scales the immune-mediated clearance term.
- Prime dose resets Ab titer to 0 (naive patient). Re-dose now keeps the current titer but restarts the blood-concentration clock at t = 0 — try priming, then raising the titer slider to ~60–80 AU before re-dosing to see delivered payload collapse.
Two competing first-order pathways remove LNPs from blood: immune/RES clearance (k_clear) and productive uptake by target hepatocytes (k_target, held constant here). Integrating dC/dt = −k_total·C together with dDelivered/dt = k_target·C gives the closed forms above exactly — verified algebraically: blood + delivered + captured always sums back to the full dose, for any k_clear/k_target ratio. The left panel shows the stochastic particle-level view (for intuition); the right-hand chart plots the exact closed-form curves the readouts are computed from.
Drag inside the loop diagram to rotate it, or scroll to zoom — this is a 2D "orbit" analog of the loop viewpoint.