You can write completely secure code and run it in a locked down VM and it won't protect you from lethal trifecta attacks - these attacks work against systems with no bugs, that's the nature of the attack.
Then again, all theoretical on my part. I keep messing around with Qubes, but not enough to make it my daily driver.
-Access to your private data
-Exposure to untrusted content
-The ability to externally communicate
Then it's not "locked down"
Depending on your security requirements you should have only one or two of those capabilities per VM