Short answer: nobody has a clean “micro/nanoplastic-resistance” haplotype you can order on Etsy. The human evidence is thin and mostly indirect. But if you zoom in on the pathways plastics and their lovely hitchhikers (phthalates, bisphenols, PAHs, PFAS stuck to the surface) actually stress, a pretty consistent genetic signature of relative resistance pops out.

Here’s the compact, lab-grade cheat sheet:

1) Oxidative-stress hardening

Micro/nanoplastics (MNPs) reliably spike ROS. Lines and animals that cope best show a primed Nrf2 program.

• Pro-resistance signature: gain-of-function in NFE2L2 (Nrf2), low-activity KEAP1 alleles, higher baseline/inducible HMOX1, NQO1, GCLC/GCLM, SOD2, GPX1/4, CAT, PRDXs expression. Mechanistically on-point across models of MNP oxidative damage and Keap1-Nrf2 engagement. PMC+2ScienceDirect+2

2) Endocytosis/uptake throttling

Cells that internalize fewer particles suffer less. Uptake of PS nanoplastics is endocytosis-dependent and cell-type specific.

• Pro-resistance signature: lower activity or expression of scavenger receptors (MSR1/SR-A1, MARCO, CD36), moderated clathrin/caveolin endocytosis genes, tighter LRP1 control. In vitro, dialing down these routes reduces PS-NP burden. PMC+1

3) Lysosome–autophagy clearance that actually works

Nanoplastics jam lysosomes. If you can digest or export the junk, you live longer.

• Pro-resistance signature: robust TFEB axis and autophagy machinery (ATG5/7, BECN1, MAP1LC3B, SQSTM1/p62) that turns over damaged cargo instead of stalling. Multiple mammalian tissues show autophagy gene induction after MNP exposure; systems with efficient flux fare better. PMC+2News-Medical+2

4) Inflammasome dampers

MNPs can trip NLRP3, leading to IL-1β signaling and pyroptosis. Overreactive inflammasomes ≠ longevity.

• Pro-resistance signature: hypoactive NLRP3 or tuned-down upstream sensors (TLR4, P2RX7), strong IL1RN and NF-κB brakes. Reviews flag NLRP3 as a central sensor for MNPs; “low responders” should be less damaged at equal dose. PMC+1

5) Efflux > influx

The more you can pump out plastic-bound organics, the less intracellular chaos.

• Pro-resistance signature: high-function ABCB1 (P-gp), ABCC1-3 (MRPs), ABCG2. Caveat: some plastic-related chemicals inhibit these pumps; variants that resist inhibition would be protective. PMC+2MDPI+2

6) Barrier integrity genes

A decent epithelium beats heroics downstream.

• Pro-resistance signature: sturdy tight-junctions (CLDN1/4, OCLN, TJP1), mucins (MUC2) and cilia genes that limit particle penetration. Strong barriers blunt uptake and inflammation in airway and gut models; epidemiology is catching up. PMC+1

7) Detox receptors for the leachate cocktail

A lot of the toxicity is actually the chemicals riding the plastic.

• Pro-resistance signature: responsive but not hypertoxic AHR axis (for PAHs), plus competent CYP1A1/1B1, and tuned PXR (NR1I2)/CAR (NR1I3) with downstream UGTs/GSTs. AhR-active ligands have been measured on plastic pellets; better biotransformers handle the load. Frontiers+1

8) Ferroptosis brakes and mitochondrial QC

Some MNP injuries look ferroptotic and mito-centric.

• Pro-resistance signature: resilient GPX4, SLC7A11, iron-handling genes (FTH1/FTL, SLC40A1), plus PINK1/PARK2 mitophagy to cull damaged mitochondria. Recent work links microplastics to ferroptosis and autophagy shifts in lung and other tissues. PMC

9) DNA repair sanity

If particles or their co-pollutants nick DNA, repair capacity limits long-term risk.

• Pro-resistance signature: competent BER/NER/DSB modules (OGG1, PARP1, XPA–G, ATM/ATR, BRCA1/2). Reviews consistently report genotoxic signals with MNP exposure. ScienceDirect

10) Mixture tolerance

PFAS plus microplastics can be nastier than either alone. Resistance means surviving mixtures, not single toxins.

• Pro-resistance signature: the whole set above, because synergy tends to exploit weak links. The Guardian

What this means practically

• There is no validated human “resistance genotype” yet. No GWAS of MNP outcomes as of 2025. Most signals are from transcriptomics, perturbation assays, and animal models. Treat what’s above as a candidate resistance panel, not gospel. PMC+1

• Best-in-class resistance looks like: low uptake, high efflux, fast autophagy/lysosomal turnover, quiet inflammasome, aggressive antioxidant tone, tight barriers, and decent repair.

If you’re designing screens

1. CRISPR-pooled survival/uptake screens with fluorescent PS-NPs to hit endocytosis and lysosome genes.

2. Reporter lines for Nrf2, NF-κB, TFEB, and caspase-1 to rank protective edits or compounds.

3. Ferroptosis assays under MNP exposure with GPX4/SLC7A11 modulation.

4. Multi-omics with mixture exposure (MNP + PFAS/PAHs) to avoid chasing single-toxicant ghosts. The Guardian+3PMC+3PMC+3

A few concrete gene buckets to watch

• Uptake: MSR1, MARCO, CD36, LRP1, CAV1, CLTC. PMC+1

• Detox & efflux: NFE2L2, KEAP1, HMOX1, NQO1, ABCB1, ABCC1-3, ABCG2. PMC+1

• Autophagy/lysosome: TFEB, ATG5/7, BECN1, SQSTM1, LAMP1/2. PMC+1

• Inflammation: NLRP3, P2RX7, TLR4, IL1B, IL1RN. PMC

• Ferroptosis/mito: GPX4, SLC7A11, ACSL4, FTH1, PINK1, PRKN. PMC

• Barrier: CLDN1/4, OCLN, TJP1, MUC2, FOXJ1 (cilia). PMC+1

• Leachate metabolism: AHR, CYP1A1/1B1, NR1I2, NR1I3, UGTs, GSTM1/T1. Frontiers+1

If you were hoping for a single mutation that turns you into a Teflon-coated sea cucumber, sorry. Biology is petty like that: resistance is polygenic, pathway-level, and context-dependent. But if your system shows the signatures above, you’re trending toward the “shrug and keep functioning” end of the MNP spectrum.