Do you have any individuals with DOE expertise or experience in your company? My suggestion is to develop multiple plans, evaluating each for what effects can be estimated, ease of execution, what isn't in the study, resource requirements. Then predict ALL possible outcomes from each potential plan. Compare potential for knowledge gained vs. cost to gain knowledge. Then pick one and run it.
I don't know if you tried searching on previous posts/threads. For example:
https://community.jmp.com/t5/Discussions/Mixture-Design-14-factors-or-more-some-needs-to-be-equal-to...
Although not directly comparable, there are a number of references in that thread that would be good to read.
For your scenario (again I still don't know all of the variables in the process), is it possible to run an experiment on the factors you think might affect the nanoparticle formulation and create multiple "batches" of the nanoparticle formulation (also don't understand why this can't be measured (e.g., particle size, distribution of particles, chemical composition, etc.))? Then, for each batch made from the first experiment, split those batches into smaller samples and run the second experiment on each of those samples (the number of samples would be dependent on the number of treatments in the subplot experiment). This would give you the whole plot for the first experiment and the subplot of the second experiment. Also you would be able to assess the interactions between the whole plot factors and the subplot factors. So it is essentially 2 experiments merged together and executed sequentially.
"All models are wrong, some are useful" G.E.P. Box