What layout technique would you apply to reduce substrate noise coupling in a densely packed mixed-signal block?

I would go with guard rings around the sensitive analog blocks. For example, if you have an op-amp next to digital logic, placing an n+ or p+ guard ring tied to ground or VDD can collect noise currents and stop them from entering the analog side. It’s like building a fence to keep the noise out.

In my opinion, the best way is to use deep n-well isolation. When you put your analog circuit inside a deep n-well, it gets separated from the digital substrate. For instance, an ADC placed in a deep n-well will see much less substrate noise from the nearby digital switching circuits. 

We should combine multiple techniques. Using separate substrate contacts, guard rings, and proper floorplanning helps a lot. For example, placing noisy digital circuits farther from sensitive analog blocks and surrounding them with guard rings ensures better noise isolation. It may cost more area, but it gives cleaner performance.