Table 2.

A summary of the complexities, reproducibility challenges, and prospective solutions related to various BDSs.

BDS	Complexity and Reproducibility	Prospective Solutions
Liposomes	Diverse lipids induce variability. Sustained stability is challenging. Surface alterations cause variability. Scaling up adds variability.	Advanced lipid-mixing technologies. Freeze–thaw increases reproducibility. Advanced ligand conjugation methods. Automated production control.
Protein- b ased NPs
Albumin NPs	Influenced by albumin source. Uniform size and shape are difficult to attain. Altered surface for specific targeting. Efficient drug encapsulation control.	High-pressure homogenization. Improved purification techniques. High-throughput screening. Microfluidics and computational modeling.
Protein-based nanocages	Ensuring consistent protein folding. Reproducible encapsulation. Stable surface chemistry. Efficient drug encapsulation control. Consistent drug release profiles.	Advanced bioengineering methods. Monitoring protein folding in real-time. New modification methods for stability. Innovative drug-loading for consistency. Smart release systems for specific triggers.
VLPs	Complexity in VLP assembly. Attaining purity and reproducibility. Heterogeneous surface modifications. Inconsistent therapeutic encapsulation in VLPs.	Advanced purification such as SEC. Genomic engineering for optimized production. Developed specific bioconjugation techniques. High-throughput techniques for optimal encapsulation.
NDs	Component multiplicity causes variability. Consistent size and shape. Adding functional groups increases complexity. Batch-to-batch variability	Synthesis and purification for uniformity. Advanced assembly techniques. Site-specific functionalization and modular design. Standardized protocols, real-time QC, and advanced characterization.
Silk Fibroin and Gelatin	Source variability affecting properties. Controlling degradation profile. Ensuring efficient encapsulation. Batch-to-batch variability due to natural sourcing. Sensitivity to processing conditions leading to variability.	Implement strict source control and purification processes. Crosslinking and site-specific functionalization. Develop recombinant alternatives. Standardizing protocols. Quality assurance measures. Process analytical technology (PAT).
EVs	Heterogeneity of EV populations. Differentiating EV subtypes is challenging. Possible contamination with proteins. Ensuring efficient encapsulation. Controlling release kinetics. Maintaining EV properties post-modification. Ensuring targeting specificity. EV source depends on donor cells.	Advanced centrifugation. High-resolution imaging and flow cytometry. Improved purification processes. Sonication or electroporation. Covalent and non-covalent linking. Bio-orthogonal chemistry. Molecular imprinting techniques. Standardized cell lines/biofactories.
CMDNs	Potential heterogeneity due to cell sources. Unpredictable biological interactions. Batch-to-batch differences. Enhanced nanocarrier functionality/specificity.	Improved cell culture techniques. Predictive molecular modeling and simulation. Controlled nanocarrier production via microfluidics. Surface engineering, genetic modifications, molecular tethering strategies.
Polysaccharides
Alginate	Variability in alginate source/purity. Gelation process control. Encapsulation efficiency variability.	Advanced chromatography for purification. Microfluidics for consistent gel bead formation. Advanced sonication/emulsification.
Chitosan	Molecular weight influences properties. Degree of deacetylation influences properties. Replicating desired structures is challenging. Crosslinking variability affects stability. Uniform surface properties are challenging.	Advanced chromatographic techniques to standardize molecular weight. Spectroscopy for precise deacetylation. High-resolution microscopy and automated synthesis. Advanced controlled crosslinking techniques. Advanced surface characterization.
Hyaluronic acid	Variability in sources. Consistent molecular weight is crucial.	Microbial synthesis of HA for consistency. Real-time molecular weight monitoring.
Dextran	Variability in molecular weight distribution. Branching variation affects behavior. Functional group variation. Achieving consistent size/morphology is challenging.	Controlled polymerization methods. Detailed structure analysis via spectroscopy. Controlled enzymatic/chemical modifications. Microfluidics for controlled and reproducible nanosystem generation.