Leaky vessels, poor drainage
A growing tumour demands a fast blood supply, so it triggers rapid, disorganised vessel growth. These new vessels are sloppily built: their walls have gaps that healthy vessels do not, sometimes hundreds of nanometres wide. At the same time the tumour's lymphatic drainage — the system that normally clears fluid and large particles from tissue — is poor or missing. Put the two together and you get the enhanced permeability and retention (EPR) effect: particles of the right size leak out of the blood into the tumour (enhanced permeability) and then stay there because nothing drains them away (retention).
Because EPR needs no homing molecule — it works purely on size and the tumour's faulty plumbing — it is the textbook engine of passive targeting. A small free drug molecule diffuses freely in and out everywhere and gets no benefit. But package that drug inside a nanoparticle or liposome of, very roughly, 10 to 200 nm, and the carrier becomes too big to leave normal vessels yet small enough to slip through tumour gaps.
Staying in circulation long enough
EPR is slow: it can take many hours for enough carrier to seep into the tumour. That only works if the carrier survives in the blood that long. Unprotected particles are quickly recognised as foreign and swept out by the liver and spleen within minutes. The fix is PEGylation — coating the surface with flexible polyethylene-glycol chains that form a watery shield, hiding the particle from clearance. The result is a long-circulating stealth nanoparticle that lingers in the blood, giving EPR time to act.
Surface area to volume — why small carriers leak and big ones do not
A particle slips through a vessel gap only if it is smaller than the gap.
Healthy vessel junctions ~ <2 nm (tight); tumour gaps ~ 100-800 nm.
Design window for EPR carriers:
too small (<8 nm) -> cleared by kidney filtration, gone in minutes
sweet spot -> ~10-200 nm: stays in normal vessels, leaks into tumour
too large (>400 nm) -> trapped/cleared, poor circulation
Worked check: a liposome of diameter d = 100 nm
radius r = 50 nm -> passes 100-800 nm tumour gaps = YES leaks in
cannot cross <2 nm healthy junctions = stays in blood
Conclusion: 100 nm sits inside the EPR design window. Good.