Inference-Time Steering Across Scaffolds and Epitopes for Sample-Efficient De Novo Nanobody Design

Scientific design often requires jointly satisfying multiple objectives and constraints. Pretrained masked diffusion models provide a generative foundation for this task, but fine-tuning them to meet these objectives and constraints incurs additional training costs, motivating inference-time guidance with frozen models. However, such guidance faces two challenges: pass-or-fail constraints and black-box reward models may provide no useful gradients, while jointly satisfying multiple requirements can leave a small feasible region, making feasible designs difficult to find within a limited inference budget. To address these challenges, we introduce DiMOS, a training-free framework for multi-objective scientific design. Using joint rewards from candidate completions, DiMOS performs approximate Doob-guided local resampling without requiring reward gradients. To allocate computation efficiently, it uses budget-efficient trajectory search to focus computation on promising continuations. Across six DNA, protein, and RNA tasks, DiMOS attains the highest joint success rate at comparable generation times, up to $1.98\times$ the strongest baseline on DNA and protein, while maintaining high sequence uniqueness and naturalness.

Molecular optimization in drug discovery, materials design, and catalysis requires searching vast chemical spaces under tight evaluation budgets, since high-fidelity oracles and experimental measurements are costly. The practical impact of an optimization method therefore hinges on its sample efficiency: how few evaluations it needs to find strong candidates. We introduce Sample Efficient Generative Optimization (SEGO), a framework for Bayesian optimization on adaptively generated molecules. In SEGO, a probabilistic surrogate model forms a hypothesis about where hits lie in chemical space, a generative model is steered to propose candidates in that region, the most promising candidate is selected via an acquisition function, and the resulting oracle call is used both to sharpen the surrogate and to anchor the generator in real reward. SEGO attains state-of-the-art performance on the practical molecular optimization (PMO) benchmark using only one tenth of the oracle calls consumed by other methods, and on a multiparameter docking task it reaches ten hits in roughly half the oracle calls of existing approaches. These gains move molecular optimization closer to campaigns driven by direct experimental feedback.

We study inference-time control for text generation in discrete diffusion language models, where the goal is to steer sampling toward sequence-level rewards without retraining. Prior work in this domain has focused on particle-based methods such as best-of-$n$ sampling and bootstrap sequential Monte Carlo, which may suffer from overoptimism and weight degeneracy, respectively. We address these limitations using \emph{nested} sequential Monte Carlo methods. We formulate nested SMC (NSMC) and fully-adapted nested SMC (FA-NSMC) for Feynman--Kac steering, identifying and correcting errors in prior formulations that lead to biased final estimates. We evaluate these methods on toxicity and fluency steering tasks, showing that NSMC and FA-NSMC consistently outperform best-of-$n$ and bootstrap SMC.