Accelerating the Development of PLGA In Situ Forming Depots Through AI-Driven Multi-Objective Optimization

Self-emulsifying drug delivery systems (SEDDS) can improve the oral bioavailability of poorly soluble drugs, but identifying high-performing formulations remains experimentally intensive. We present Andromeda 2, an agentic system that reasons over structured in-house experimental evidence and invokes computational and experimental tools to design and execute successive formulation batches. Using a miniaturized automated laboratory at a matched budget, we benchmark it against Andromeda 1, a probabilistic optimization model deployed across dozens of live development projects, and a wet-lab design-of-experiments (DoE) campaign. For paclitaxel, Andromeda 2 achieved a 50% high-performance hit rate versus 17% for Andromeda 1 and 2% for DoE, and identified 12 formulations meeting all four target product profile (TPP) objectives versus 6 and 0, respectively. Median $AUC_{10-240}$ was 70.1, 12.0, and 3.5 mg$\cdot$min/mL, while maximum AUC was comparable between Andromeda 2 and Andromeda 1. A selected full-TPP formulation achieved an apparent effective paclitaxel loading of $19 \pm 5\%$ w/w at the first FaSSIF measurement, approximately 3.3-fold higher than the 5.7% w/w loading reported for a published paclitaxel S-SEDDS. A controlled ablation showed that access to structured in-house experimental evidence increased mean AUC by 34%.

Cold-chain storage limits access to insulin for hundreds of millions of people; a thermally protective patch polymer could help, but the design space is too large for exhaustive experiment. Starting from that problem, we narrow to an agentic workflow: a large language model (LLM) calls physics-based tools through the Model Context Protocol (MCP), searching the discrete PSMILES space under a budget of OpenMM Packmol-matrix evaluations. The LLM acts as an implicit acquisition function conditioned on a persistent "discovery world": hypotheses, literature claims, and simulation outcomes updated each iteration. Under matched oracle budgets, the best autonomous campaign reaches an insulin-polymer interaction energy of -2263 kJ/mol, outperforming reinforcement-learning baselines by 68% and Bayesian optimization by 19%. Three independent campaigns converge on one structural motif (dense hydrogen-bond donors and acceptors per repeat unit) while physics checks reject infeasible packings and name-structure mismatches before they steer the next step. The science stage is CPU-bound and runs on commodity hardware. More broadly, the same architecture and workflow designed here applies to other protein-stabilization tasks whenever a tractable screening oracle is available.

Polymeric materials underpin modern technologies spanning energy storage, microelectronics, healthcare and sustainable manufacturing. Yet their rational design remains exceptionally challenging because material performance emerges from complex interactions among molecular composition, chain architecture, processing history and hierarchical structural evolution across multiple length and time scales. Consequently, polymer research has long relied on labor-intensive experimentation and fragmented modeling approaches, limiting both mechanistic understanding and innovation efficiency. Recent advances in data infrastructure, machine learning, large artificial intelligence (AI) models and laboratory automation are beginning to reshape this landscape. Rather than functioning as isolated tools, polymer databases, predictive models, AI agents and automated laboratories are increasingly converging into interconnected discovery ecosystems. As a result, the central challenge is shifting from improving predictive accuracy alone to enabling reliable decision-making, adaptive learning and seamless integration across computation, experimentation and scientific reasoning. We argue that polymer science is entering an era of autonomous discovery, in which data, simulation, reasoning and experimentation operate within self-improving feedback loops that continuously generate hypotheses, design materials, execute experiments and refine predictive models. By unifying molecular design, process optimization, experimental validation and industrial translation, such autonomous ecosystems establish a more predictive, reproducible and scalable paradigm for polymer innovation, fundamentally transforming how polymer research is conducted.