首个支持非标准氨基酸的肽段从头设计框架，提升药物亲和力与可设计性。

Peptide drugs incorporating non-standard amino acids (NSAAs) offer improved binding affinity and improved pharmacological properties. However, existing peptide design methods are limited to standard amino acids, leaving NSAA-aware design largely unexplored. We introduce NS-Pep, a unified framework for co-designing peptide sequences and structures with NSAAs. The main challenge is that NSAAs are extremely underrepresented-even the most frequent one, SEP, accounts for less than 0.4% of residues-resulting in a severe long-tailed distribution. To improve generalization to rare amino acids, we propose Residue Frequency-Guided Modification (RFGM), which mitigates over-penalization through frequency-aware logit calibration, supported by both theoretical and empirical analysis. Furthermore, we identify that insufficient side-chain modeling limits geometric representation of NSAAs. To address this, we introduce Progressive Side-chain Perception (PSP) for coarse-to-fine torsion and location prediction, and Interaction-Aware Weighting (IAW) to emphasize pocket-proximal residues. Moreover, NS-Pep generalizes naturally to the peptide folding task with NSAAs, addressing a major limitation of current tools. Experiments show that NS-Pep improves sequence recovery rate and binding affinity by 6.23% and 5.12%, respectively, and outperforms AlphaFold3 by 17.76% in peptide folding success rate.