arXiv:2509.14287v1 Announce Type: cross Abstract: Biological sequence design (DNA, RNA, or peptides) with desired functional properties has applications in discovering novel nanomaterials, biosensors, antimicrobial drugs, and beyond. One common challenge is the ability to optimize complex high-dimensional properties such as target emission spectra of DNA-mediated fluorescent nanoparticles, photo and chemical stability, and antimicrobial activity of peptides across target microbes. Existing models rely on simple binary labels (e.g., binding/non-binding) rather than high-dimensional complex properties. To address this gap, we propose a geometry-preserving variational autoencoder framework, called PrIVAE, which learns latent sequence embeddings that respect the geometry of their property space. Specifically, we model the property space as a high-dimensional manifold that can be locally approximated by a nearest neighbor graph, given an appropriately defined distance measure. We employ the property graph to guide the sequence latent representations using (1) graph neural network encoder layers and (2) an isometric regularizer. PrIVAE learns a property-organized latent space that enables rational design of new sequences with desired properties by employing the trained decoder. We evaluate the utility of our framework for two generative tasks: (1) design of DNA sequences that template fluorescent metal nanoclusters and (2) design of antimicrobial peptides. The trained models retain high reconstruction accuracy while organizing the latent space according to properties. Beyond in silico experiments, we also employ sampled sequences for wet lab design of DNA nanoclusters, resulting in up to 16.1-fold enrichment of rare-property nanoclusters compared to their abundance in training data, demonstrating the practical utility of our framework.