multiple objects

Yes, you can open multiple objects in Designer and set the output nodes to point to particular objects. Right click on an output node and choose 'View in 3D View' and you will get a choice of which model and which use for the node.

However, the graph could become quite complex, even when using sub-graphs.

From a workflow point of view, I prefer to play to the strengths of individual packages. Therefore I:

a. Create the models in a 3D application (you mention Blender which works well for this).
b. Unwrap the models in the 3D application and export them as fbx (either just high poly or high and low poly depending on final use)

c. I import those to Substance Painter where I bake then add materials and textures to the models. Painter can handle multiple objects, provided your PC spec is up to it.
d. If a material is required that I do not have, then I make it in Substance 3D Designer and publish it to Painter for application to the model(s)

e. After exporting the finished textures from Substance Painter I apply them to the models back in the 3D app. If using Blender, then the Node Wrangler plug in makes this a quick process.

f. Finally I light and render, before compositing (which I prefer to do in Photoshop).

Dave