If `<directory of python.exe>\Lib\os.py` exists, then you shouldn't need either a registry entry or environment variable.

This sounds the same as the approach used on GitHub Actions and Azure Pipelines, and also through the packages at https://www.nuget.org/packages/python. These work fine, as far as I'm aware.

If there is some other reason you need PYTHONHOME to be set inside an activated virtual environment, you could set it _after_ activating the environment, or just modify the Activate.ps1 that is included in your tarball.

However, I seem to recall there were some fairly obscure bugs if a venv didn't resolve itself normally. So your best bet is to make sure that it can be resolved without needing the setting.