Francisca G. Perfeito, M Oliveira, João F. Mano
Polymer geometry is a primary determinant of physical behavior and biological performance. Beyond conventional spherical and bulk morphologies, unconventional three-dimensional (3D) architectures - ranging from anisotropic particles and fibers to complex membrane-based systems - have emerged as powerful tools for biomedicine. Advances in fabrication methods, including microfluidics, lithography, and physical deformation techniques, now enable precise control of particle shape, anisotropy, and compartmentalization at the nano- and microscale. These geometrical cues strongly influence critical biological processes such as cellular adhesion, phagocytosis, biodistribution, and immune activation, while also modulating drug release, tissue targeting, and responsiveness to external stimuli. Bioinspired designs, including red-blood-cell-like discoids, microneedles, and helical fibers, exemplify how shape engineering can enhance circulation time, mechanical adaptability, and improve integration with biological systems. Moreover, membrane-based polymersomes and multicompartment capsules extend this paradigm by introducing hierarchical organization and dynamic shape transformation. This Review focuses on the most recent advances in the design, fabrication, and biomedical translation of polymeric structures with unconventional geometries, highlighting the interplay between form and function as a central principle in next-generation biomaterials. Ultimately, controlling shape across scales offers unprecedented opportunities to develop responsive, multifunctional, and clinically relevant polymeric systems.