I haven't completely thought through this, but I can see issues with porting PIO-USB [0] for example. USB relies on a few different pulls to Vcc and Gnd with pre-defined values. On the host side you have to pull your signal lines to ground with 15k resistors. Those aren't strong enough to overcome the current leakage. The tricks where you enabled pad inputs only when you're reading the pin don't work here either as you can't do that in PIO.
Things like logic analyzers are going to have similar issues where their inputs will have to be buffered to provide a suitably low impedance path.
It's not insurmountable but it's enough for me to just fall back on the RP2040 in situations where I don't want to spend the effort to validate the RP2350.
It's not an issue for PIO-USB, since the pullup/pulldowns in USB are just used for device and speed detection. And for the pulldowns to do anything the pins have to be high impedance which you can't do in PIO code anyway. So just making sure to drive the pins low for 1 cycle before putting them in high impedance mode is sufficient as a workaround.
Could be an issue for logic analyzers, though usually you'd have a voltage translator in front of that anyway.
Things like logic analyzers are going to have similar issues where their inputs will have to be buffered to provide a suitably low impedance path.
It's not insurmountable but it's enough for me to just fall back on the RP2040 in situations where I don't want to spend the effort to validate the RP2350.
0: https://github.com/sekigon-gonnoc/Pico-PIO-USB