Contemporary synthetic chemistry approaches can be used to yield a range of distinct polymer topologies with precise control. The topology of a polymer strongly influences its self-assembly into complex nanostructures however a clear mechanistic understanding of the relationship between polymer topology and self-assembly has not yet been developed. In this work, we use atomistic molecular dynamics simulations to provide a nanoscale picture of the self-assembly of three poly(ethylene oxide)-poly(methyl acrylate) block copolymers with different topologies into micelles. We find that the topology affects the ability of the micelle to form a compact hydrophobic core, which directly affects its stability. Also, we apply unsupervised machine learning techniques to show that the topology of a polymer affects its ability to take a conformation in response to the local environment within the micelles. This work provides foundations for the rational design of polymer nanostructures based on their underlying topology. Our molecular dynamics simulations provide molecular-scale understanding of how polymer topology effects the self-assembly and stability of nanoparticles, and the polymer molecule’s ability to take a conformation in response to its local environment. Ring polymers are one synthetically accessible topology that have drawn considerable attention as a result of the unique properties that they exhibit in comparison to their linear counterparts.5–13 Functional polymer nanostructures have been typically fabricated using linear polymers but significant synthetic advances in the past two decades have made ring copolymer synthesis possible. Ring polymers demonstrate distinct self-assembly behavior,9,12,13 which leads to their resultant micelles possessing markedly different properties,9 including the size and shape,14 morphology,15,16 temperature, salt tolerance,17,18 and degradation14 with respect to micelles formed from analogous linear polymers.The ability of amphiphilic polymers to self-assemble into specific morphologies in solution has driven interest in their deployment for a diverse range of applications.19,20 greater efficacy,21–24 longer in vivo circulation times,25,26 and high cancer cell uptake25–28 as the same polymers with a linear topology.In drug delivery applications, the ability to control the size and stability of micellar aggregates is particularly important. The size of such micelles is one of the most critical features in determining biodistribution and the stability can be tuned to prevent premature release or to enable a controlled release of therapeutics. Ring polymers have shown great promise as potential drug and gene delivery vehicles because they often show improved drug loading and releasing capacity,29,30 extensional flows31,32 and thin films.33,34 However, relatively few simulation studies have investigated the underlying mechanisms that lead to the properties of ring polymers in aqueous environments observed experimentally. Studies that have been performed have primarily utilized coarse-grain polymer models to gain insight into how polymer topology affects the morphology of the micelles that form.23,35–39While interest in the application of self-assembling ring polymers in drug-delivery applications is building, there is a relative lack of detailed understanding of the molecular-scale mechanisms that drive the emergence of their desirable properties. Molecular-scale simulations present the unique opportunity to build this level of understanding. Simulations have recently been used to develop understanding of the unique properties of ring polymers within polymeric melts,12EO31-)) in comparison to its analogous linear diblock topology (MA12EO30) and triblock topologies (MA-terminated (MA6EO31MA6) & EO-terminated (EO15MA12EO15))  and poly(ethylene oxide) blocks (-(MA15)) see . We provRG) and the eccentricity of the largest micelle in each system  algorithm,42 followed by clustering in the resulting embedded space using Hierarchical Density-Based Spatial Clustering of Applications with Noise (HDBSCAN)43  are found to be enriched in the core of the micelle. In these conformations, the EO block is more extended so that it can reach the micelle corona and interact with the surrounding aqueous environment. The polymers at the interface of the core of the ring polymer micelle take on a more conventional ring shape (cluster 2), allowing the EO block to expand to maximize its contact with the surrounding water and the MA block to embed into the core to minimize its interaction with water.For the diblock polymer micelle, the pattern is similar as for the cyclic one. The most extended conformations (cluster 1 and 2) are predominate in the core of the micelle. In these conformations, the MA is more extended, allowing it to maximize its contacts with the rest of the MA present in the core. Finally, cluster 3 is more likely to be found at the core–shell interface. This cluster presents a collapsed MA and extended EO, which allows the EO to maximise its contacts with the water, while the MA minimizes its contacts with this solvent by collapsing within itself.et al. have studied MA-EO-MA linear and MA-EO ring block copolymers and found that the linear polymers form micelles that have larger hydrodynamic diameters and aggregation numbers, while also being less thermally and salt stable than the corresponding ring polymer.18 The same authors also studied butyl acrylate (BA)-ethylene oxide linear and cyclic block copolymers and found that the size of the micelles from the two polymers were similar but the ring polymer showed greater thermal stability.17 Our simulations show that there are more MA–MA contacts within the core of ring polymer as compared to the MA-terminated linear polymer which results in a more compact  and more stable micelle  forms larger aggregates that are less stable than those formed from the cyclic or diblock polymer. Honda et al.17,18 as well as for Pluronics which contain blocks of propylene oxide (PO) and ethylene oxide.44 In each case, the authors suggest that these polymers with the hydrophobic monomers on the terminal ends form flower-like micelles where a majority of the polymers have both terminal ends within the core of the micelle, and some of the polymers have a hydrophobic terminal end in solution. The results of our simulations for the MA-terminated linear polymers show that ∼20% of the polymers take conformations which result in at least one of the MA-blocks being in the corona of the micelle. Interestingly, with the larger aggregation number for the MA-terminated linear polymers than for the micelles formed from the EO-terminated linear polymers, we find that both micelles have roughly the same number of MA monomers (∼360) in the core of their micelles.Our ability to identify three distinct conformations of each of the polymers allows us to provide a detailed picture of the internal structure of the micelles. In doing so, we show that for the linear polymer with the hydrophobic monomers on either end (MA-terminated linear) there are two conformations where the MA blocks are near to one another and one conformation in which the polymer is fully extended with the MA blocks separated from another. This is consistent with the general picture suggested for the MA-EO and BA-EO polymers studied by Honda We found that in the micelles formed by the EO-terminated triblock, the diblock and the ring polymers, which have a well defined core and corona, the polymers take different conformations depending on their location within the micelle. In the case of the EO-terminated linear polymer we find that the polymers in the core of the micelle have a propensity to have an elongated MA block which maximizes the hydrophobic contact between MA monomers and more compact EO blocks which lie on the surface of the micelle. The polymers at the core/shell interface of the micelle have more compact MA blocks which allows the polymers to more effectively shield their hydrophobic blocks and the EO blocks are more extended in order to maximize their hydration. While in the ring polymer micelle, we find two more elongated conformations which are most prominent in the core of the micelle, whereas the other more ring-like conformation sits at the core–corona interface. These conformations taken by the ring polymers in the different parts of the micelles allow the polymers to maximize the hydrophobic contact of the MA blocks while also allowing the EO monomers to maximize their interaction with the surrounding water. In the case of the diblock polymer micelle, we find that the conformations where the MA blocks are the most extended are located closer to the core, while the conformation with a collapsed MA block is found close to the core–shell interface. Then, it is clear that these conformations are the result of the MA monomers maximising their hydrophobic interactions and minimising their contact with the aqueous environment. Therefore our findings show that polymers that can take location specific conformations will form stable micelles that have hydrophobic cores which are shielded by the hydrophilic monomers, and those that cannot, the MA-terminated polymer in this case, will not.45–47Our simulations provide a mechanistic picture of what leads to the difference in size and stability of micelles formed by block copolymers that differ in topology but not in the chemical composition of their constituent monomers. Additionally, we have been able to demonstrate the range of conformations that are taken by four different topologies of polymers within the micelle and how they determine the stability of the micelles. We have also shown how the conformations of the polymers change as their position within the micelle changes, which is particularly interesting when considering loading these micelles with small molecule therapeutics, as the location and the hydration of the drug within the micelle will be driven largely by the conformations of the polymers in its local environment. This understanding allows polymer topology to become another parameter that can be used to perform rational design of polymer nanoparticles for the use in a variety of applications including drug delivery.48 to describe the interactions of the polymers and the TIP3P water model.49 All of the simulations were performed using GROMACS50 versions 2019.2 and 2020.4. The same simulation protocol was followed for each of three simulations, which begins with energy minimization by steepest descent, followed by a 125 ps simulation in the NVT ensemble using the Nosè–Hoover thermostat to control the temperature (target temperature 300 K) with a timestep of 1 fs. Subsequently we ran 1 μs production simulations in the NPT ensemble using the Nosè–Hoover thermostat and the Parrinello–Rahman barostat to control the temperature (target temperature 300 K) and pressure of 1 atm, respectively with a 2 fs timestep while all hydrogen-containing bonds were constrained using the LINCS algorithm.51 In all simulations, the non-bonded interactions were cut off at 12 Å while the particle-mesh Ewald (PME) algorithm was used to calculate long-range electrostatic interactions. Appropriate burn-in times were calculated, with only the stationary portion of the production simulations used for analysis. A description of all of the analyses conducted on these simulations is described in the ESI.†Each simulation reported consists of 20 polymers placed in a simulation box with initial dimensions of 147 Å × 147 Å × 147 Å containing approximately 105 000 water molecules, resulting in 3 wt% solutions of each polymer. We used the OPLS forcefield parameters as prescribed by the PolyParGen webserverRaquel López-Ríos de Castro: data curation, formal analysis, investigation, methodology, software, validation, visualisation, writing – original draft. Robert M. Ziolek: conceptualization, formal analysis, methodology, software, supervision, writing – review & editing. Christian D. Lorenz: conceptualization, funding acquisition, project administration, resources, supervision, writing – review & editing.There are no conflicts to declare.NR-015-D3NR01204B-s001