I've never used Qubes. Rather I heavily segment with manually configured VMs. The ones that run proprietary software (eg webbrowsing, MSWin, etc) generally run on a different machine than my main desktop. It's quite convenient as I can go from my office to the couch, and I just open up the same VMs there and continue doing what I was doing.

I define the network access for each VM in a spreasheet (local services and Internet horizon), which then gets translated into firewall rules. I can simultaneously display multiple web browsers, each with a different network nym (casual browsing, commercial VPN'd, TOR, etc).

The downsides include needing an ethernet cable on my laptop (latency), and that this setup isn't great at going mobile. Eventually I'll get around to setting up a medium-trust laptop that runs a web browser and whatnot directly (while not having access to any keys to the kingdom), one of these days real soon now.

Which brings me to the real downside is the work required to administer it - you already have to be in the self-hosting game. This is where an out-of-the-box solution could excel. Having recently become a NixOS convert, SpectrumOS looks very interesting!