It can be made to work (as you point out), and the core idea is great, but the implementation is terrible. You have to stop and think about struct layout rules rather than declaring your intent and having the compiler check for errors. As usual C is a giant pile of exquisitely crafted footguns.

A "sane" version of the feature would provide for marking a struct as intended for ser/des at which point you'd be required to spell out every last alignment, endianness, and bit width detail. (You'd still have to remember to mark any structs used in conjunction with mmap but C wouldn't be any fun if it was safe.)

You just define the structures in terms of some e.g. uint32_le etc types for which you provide conversion functions to native endianness. On a little endian platform the conversion is a no-op.