open pdf-files in an email

Give this a try: boot into Safe Mode according to How to use safe mode on your Mac and test to see if the problem persists. Reboot normally and test again.

NOTE: Safe Mode boot can take up to 3 - 5 minutes as it's doing the following; 

• Verifies your startup disk and attempts to repair directory issues, if needed

• Loads only required kernel extensions (prevents 3rd party kernel/extensions from loading)

• Prevents Startup Items and Login Items from opening automatically

• Disables user-installed fonts 

• Deletes font caches, kernel cache, and other system cache files

First, there is no reason to ever install or run any 3rd party "cleaning", "optimizing", "speed-up", anti-virus, VPN or security apps on your Mac.  This user tip describes what you need to know and do in order to protect your Mac: Effective defenses against malware and other threats - Apple Community.  

There are no known viruses, i.e. self propagating, for Macs.  There are, however, adware and malware which require the user to install although unwittingly most of the time thru sneaky links, etc.   

Anti Virus developers try to group all types as viruses into their ad campaigns of fear.  They do a poor job of the detecting and isolating the adware and malware.  Since there are no viruses these apps use up a lot of system resources searching for what is non-existent and adversely affect system and app performance.

There is one app, Malwarebytes, which was developed by a long time contributor to these forums and a highly respected member of the computer security community, that is desshoigned solely to seek out adware and known malware and remove it.  The free version is more than adequate for most users.  

Also, unless you're using a true VPN tunnel, such as between you and your employer, school or bank's servers, they are useless from a privacy standpoint.  Read these two articles: Public VPN's are anything but private and Former Malware Distributor Kape Technologies Now Owns ExpressVPN, CyberGhost, Private Internet Access, Zenmate, and a Collection of VPN “Review” Websites. 

That being said uninstall CleanMyMac according to the developer's instructions. Also ExpressVPN.

Make sure you get all of the supporting files for each of those apps. One way I do it is to use AppCleaner.

WARNING: If you use AppCleaner on an app that you have other apps from the same developer, like Adobe, you must be extremely careful checking all checkboxes and deleting.  Some for those files may support other apps from the same developer and deleting them can mess them up.  Adobe apps is a primary example. I know from experience.  For singular apps from a developer it's safe.

kmc60 wrote:

However, once I rebooted again to normal, the problem returned.

That tells us that there's some 3rd party software that's causing the problem. Therefore download and run Etrecheck.  Copy and paste the results into your reply. Etrecheck is a diagnostic tool that was developed by one of the most respected users here in the ASC and recommended by Apple Support  to provide a snapshot of the system and help identify the more obvious culprits that can adversely affect a Mac's performance.

IMPORTANT:

Before running Etrecheck assign Full Disk Access to Etrecheck in the first window that comes up so that it can get additional information from the Console and log files for the report:

Also click the About… vurron and read the info to further permit full disk access.

Copy the report

and use the Additional Text button to include the report in your reply.

Then we can evaluate the report and see if we can determine what's causing the problem.

I have the same problem that started only recently, though I'm not sure of the trigger. I can no longer open PDFs directly in my mail (I can work around by downloading the PDF and then opening it). I did try a safe boot and the problem disappeared while booted in safe mode. However, once I rebooted again to normal, the problem returned. I'm running the latest Big Sur and was on Big Sur when this problem first surfaced a few weeks ago.

Thanks for the feedback and I believe it is good advice. The only one I’d quibble with is the vpn, although my argument mostly applies to my other iOS portable devices.

Nonetheless, where I’m not connecting the dots is what any of these has to do with my inability to open pdfs from mail directly? That error started showing up in the last 3 weeks whereas the other items mentioned have literally been in place > a year (mostly >> 1 year) and multiple macOS versions.. What DID change over the last few weeks was that I started getting weird errors that I eventually traced back to VERY low storage left on my primary “Macintosh HD” volume. As in a couple hundred MB avl on a 2TB volume…. It was surprisingly difficult to identify the problem since I was getting weird one-off errors. However, once I did figure it out, I moved my (Parallels) VMs off the main drive along with lots of video data. All is now well…except could this pdf problem be a side-effect of this out of storage problem? If so, any suggestions?

I just installed the latest Big Sur update (11.6.7) and guess what? I can once again open PDFs from Mail.

Per support.apple.com:

macOS Big Sur 11.6.7

macOS Big Sur 11.6.7 fixes an issue where Mail and apps, such as Microsoft Outlook, cannot open attachments if the app required to open the file is already running.

Thanks much for the detailed info. I downloaded and ran the free version. I'm about go through the details of the report and pursue any potential recommendations. In parallel, I'll share it here.

So giving preview full disk access fixed it for you? I tried the same thing (giving preview full disk access) but it did not seem to make a difference.