Applying when no posted openings?

So I've had decent success getting multiple round interviews with various research groups in my city simply by emailing a package to postings as I find them, and even got an offer for one but that didn't work out. Nothing sketchy on either party, just wasn't meant to be. So now I'm looking for more opportunities again but in the last month there hasn't been a single posting on any of my usual sources. I'm considering just firing off something to each group in town regardless, and playing that game.

So what's the etiquette? Cold emails, try to befriend people, then pass off a resume? Or is it reasonable to just send off a properly worded cover letter, attach the resume, and hope an MD bites? I've been cold messaged at my current position and know there's a fine line between ambitious, annoying, and straight up desperate.