Species-Specific Susceptibility of Planktonic and Biofilm Forming <em>Candida</em> Strains to Cyclodextrin-Encapsulated Essential Oils

Background/Objectives: Essential oils (EOs) have multi-target antifungal activity, but their translation is limited by volatility and poor aqueous dispersibility. Randomly methylated β-cyclodextrin inclusion (RAMEB) may enhance effective exposure and thereby alter susceptibility, stress responses, and biofilm outcomes in a species-dependent manner. This study quantified species-specific planktonic and biofilm susceptibility to four EOs and their RAMEB complexes across clinically relevant Candida species. Methods: Lavender (L), lemon balm (B), peppermint (P), and thyme (T) oils and their RAMEB complexes (RL, RB, RP, RT) were tested against C. albicans, and non-albicans Candida. Susceptibility thresholds were used to derive phase plasticity metrics. Functional inhibition was assessed via planktonic metabolism/viability and established-biofilm metabolism/viability/biomass. Mechanistic signatures were captured by ROS/RNS measurements and qPCR of antioxidant genes (CAT1, GPX1, SOD1). Mixed-effects models and multivariate/unsupervised and interpretable classification approaches (k-means, PCA, CRT) were used to integrate endpoints and stratify response phenotypes. Results: Susceptibility thresholds were strongly species-structured (lowest MIC90/EC10 for C. albicans; higher thresholds and broader sublethal windows in non-albicans species). RAMEB complexation produced formulation-dependent shifts in efficacy, with RT emerging as the most consistent broad-spectrum inhibitory condition across compartments. Biofilm biomass was comparatively insensitive even when viability was suppressed, indicating decoupling of structural biomass from biocidal activity. Mechanistic signatures were broadly conserved across species and linked to antioxidant-program engagement, with CAT1-related rules contributing to responder/tolerant classification. Conclusions: Integrating MIC/EC plasticity with functional and mechanistic markers supports rational selection of EO formulations; RAMEB complexation particularly RT prioritizes candidates for further pharmaceutical optimization while highlighting species-specific vulnerabilities.